Signaling through CD27 plays a role in T cell activation and memory. However, it is currently unknown how this costimulatory receptor influences CD4 effector T (Teff) cells in inflamed tissues. In the current study, we used a murine model of inducible self-antigen expression in the epidermis to elucidate the functional role of CD27 on autoreactive Teff cells. Expression of CD27 on Ag-specific Teff cells resulted in enhanced skin inflammation when compared with CD27-deficient Teff cells. CD27 signaling promoted the accumulation of IFN-γ and IL-2-producing T cells in skin draining lymph nodes in a cell-intrinsic fashion. Surprisingly, this costimulatory pathway had minimal effect on early T cell activation and proliferation. Instead, signaling through CD27 resulted in the progressive survival of Teff cells during the autoimmune response. Using BH3 profiling to assess mitochondrial cell priming, we found that CD27-deficient cells were equally as sensitive as CD27-sufficient cells to mitochondrial ...
Adoptive transfer of CD4+CD25+ T cells inhibits HSV-1-specific CD8+ T cell responses. Purified CD4+CD25+ and CD4+CD25− T cells (2 × 106/mouse) were adoptively transferred into WT B6 mice 24 h before HSV infection, and the immune response was measured on days 7 and 28 p.i. (A) On days 7 and 28 p.i., spleen cells were incubated with gB498-505, and CD8/IFN-γ production was measured by intracellular staining. The number shown in each plot is the mean percentage of IFN-γ-producing CD8+ T cells obtained from four mice per group. (B) The resulting decrease in IFN-γ-secreting CD8+ T cells in B6 mice after adoptive transfer of CD4+CD25+ T cells were also measured by a standard ELISPOT assay. On days 7 and 28 post HSV infection, spleen cells were analyzed for the number of IFN-γ-secreting CD8+ T cells in response to SSIEFARL peptide. The error bars represent the mean ± SD of four different mice in the same group. *P , 0.05 compared with HSV-infected B6 mice receiving no adoptive transfer. Without ...
Peripheral T cells, in absence of a thymus (4, 25) or when transferred to T cell-deficient hosts (5, 7, 26), are capable of considerable expansion. The sequential transfer of a T cell population into successive hosts has shown that one T cell can generate up to 1015 cells (7). This indicates that in a normal mouse, peripheral T cell division is limited by mechanisms that probably include resource competition and complex cell interactions (9). We studied the role of T cell interactions in the control of the number of peripheral CD4+ T cells. In particular, we investigated if CD25+CD4+ T cells, which exert regulatory functions (27, 28, 29, 30, 31, 32), could also govern peripheral CD4+ T cell homeostasis.. IL-2Rα−/− mutant mice are reported as a paradigm for perturbed lymphocyte homeostasis (10). The lack of the IL-2Rα was believed to impair AICD in vivo (10), to modify the balance between clonal expansion and cell death, resulting in the deregulation of both the size and content of the ...
Our data demonstrated that naive CD8 T cells expressed low levels of IL-15Rα and thus may be targets of IL-15 action. Therefore, the deficiency of naive CD8 T cells in IL-15−/− and IL-15Rα−/− mice may be due to effects on naive CD8 T cells, although thymic defects could also contribute. Nevertheless, our examination of the early CD8 T cell response to VSV infection indicated that a proportionately normal frequency of Ag-specific cells was present in IL-15−/− mice since the percentage of tetramer-positive cells was similar in IL-15−/− and normal mice 4 days after infection (Fig. 1⇑).. The increased levels of IL-15Rα expressed by activated and memory CD8 T cells were likely responsible for the observed IL-15 augmentation of the primary response and the induction of memory cell proliferation by IL-15. Although we observed that the defect in the primary response in IL-15−/− mice was more severe than that in IL-15Rα−/− mice, it is possible that IL-15 delivers signals via ...
Interleukin-2 (IL-2) stimulates both activated CD4+ and CD8+ T cells to proliferate. IL-2 signals through an identical receptor complex and promotes the same dose-dependent phosphorylation of the canonical transcription factor STAT5 in both cell types. Despite this, CD8+ T cells enter the S phase earlier and proliferate to a greater extent than do CD4+ T cells in response to IL-2. We identified distinct IL-2 signaling dynamics in CD4+ and CD8+ T cells. In IL-2-stimulated CD8+ T cells, STAT5 phosphorylation increased rapidly and was sustained for 6 hours. In contrast, CD4+ T cells had a biphasic response, with maxima at 15 min and 2 to 4 hours after stimulation. Both cell types required vesicular trafficking, but only CD4+ T cells required new protein synthesis to maintain high phosphorylation of STAT5. Two subunits of the IL-2 receptor, IL-2Rβ and IL-2Rγ, were twice as abundant in CD8+ T cells than in CD4+ T cells. Reduction of IL-2Rβ abundance by 50% was sufficient to convert CD8+ T cells to ...
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CD4+ T细胞的激活需要T细胞上的TCR和共受体(CD28或ICOS),抗原呈递细胞上的MHCII和共激活分子两对分子的分别,同时结合。仅其中一对的结合,无法产生有效的T细胞激活。理想的CD8+ T细胞激活则依赖于CD4+ T细胞的信号转导[28]。CD4+细胞可以在初级CD8 T细胞的初次免疫应答中给予帮助,并且在急性感染的后期维持CD8+ 记忆T细胞的活性。所以,CD4+ T的激活对于CD8+ T细胞的活动是有利的[29][30][31]。 相比于MHC分子上的抗原,抗原呈递细胞的共激活分子一般是由病原体的副产物、热休克蛋白或者坏死的细胞碎片诱导表达的。共刺激机制被认为可以避免自体免疫的发生,因为即使T细胞错误地结合了自体抗原,也可能因为没有受到合适的共刺激而无法正常活化。一旦T细胞被正确地活化,它的细胞表面蛋白表达就会发生巨大的改变,活化T细胞的标志蛋白包括CD69,CD71,CD25 ...
CD4+ T cells play a major role in adaptive immune responses to intracellular and extracellular microbes by regulating the functions of B cells, CD8+ T cells, an...
How to Build Up T‐Cells in Your Body. If youd like to improve your immune system, work on increasing the number of t-cells in your body. T-cells are a type of lymphocyte that will attack cells that are infected with a virus. To improve y...
Changes of CD8/HLADR+ T cells during a period of seven years HAART ( ± SD,/ μL). Patient numbers: Effective group (A) (n = 25), Ineffective group (B) (n = 18)
But does Rove really think Palin will jump in, thats shes effectively in pre-campaign mode? Sure, shes acting like a candidate, but shes done that a lot already. Think back to the bus tour. What she craves is not so much political office but attention (and an enhancement to her celebrity status, and, of course, money), and she gets a ton of attention by tantalizing us with a possible presidential run. Its an old story by now, and we shouldnt be taken in by it. Palin can appear to be on the campaign trail, can go to Iowa and steal the spotlight, and can offer herself as GOP kingmaker -- for Perry, one would think, who gives her a way out, as she has said all along that she wouldnt run if someone else suitable were to run instead, and the two are very much on the same page. That doesnt mean shes running, just that shes being herself ...
The authors have demonstrated compartment differences between T cell immunity in the bronchoalveolar space and the periphery. These include a predominant presence of effector memory T cells and regulatory CD4+ T cells in BAL, and a higher percentage frequency of antigen-specific CD4+ T cells against influenza virus, S pneumoniae and M tuberculosis in BAL compared to peripheral blood. Our data has also demonstrated that HIV-infected individuals have impaired pulmonary CD4+ T cell immunity, which is characterised by lower proportions of total CD4+ T cells and impaired antigen-specific BAL CD4+ T cell response to influenza virus and M tuberculosis antigens.. Consistent with previous observations,21 we noticed that BAL CD4+ and CD8+ T cells were predominantly of effector memory phenotype irrespective of HIV status, while peripheral blood T cell phenotypes were distributed among naive, central memory, effector memory and terminal effector. Effector memory T cells migrate to the lung following antigen ...
Interleukin (IL)-4 is considered to be essential for T helper (Th)2 cell development, yet in areas of primary T cell activation, CD4+ cells are its only source. This implies that other signals must drive the initial expression of IL-4 production. The role of CD28 co-stimulation in Th2 subset development has been described. However, in mice deficient for CD28, Th2 responses are diminished, but not abrogated. Cytokines produced within the lymphoid tissue, e.g. IL-7, may be important in the primary activation of naive CD4+ cells. We have found that human naive CD4+ cells purified from umbilical cord blood express the IL-7 receptor and respond vigorously to IL-7 during primary stimulation. Naive CD4+ cells grown in IL-4, in the presence or absence of IL-2, fail to produce Th2 cytokines upon restimulation. In contrast, IL-7 induces development of a population of T cells that produce large amounts of IL-4. Growth in IL-7 also increases IL-2-induced production of interferon (IFN)-gamma and IL-10 production. IL
T cell dysfunction in the presence of ongoing antigen exposure is a cardinal feature of chronic viral infections with persistent high viremia, including HIV-1. Although interleukin-10 (IL-10) has been implicated as an important mediator of this T cell dysfunction, the regulation of IL-10 production in chronic HIV-1 infection remains poorly understood. We demonstrated that IL-10 is elevated in the plasma of individuals with chronic HIV-1 infection and that blockade of IL-10 signaling results in a restoration of HIV-1-specific CD4 T cell proliferation, gamma interferon (IFN-γ) secretion, and, to a lesser extent, IL-2 production. Whereas IL-10 blockade leads to restoration of IFN-γ secretion by HIV-1-specific CD4 T cells in all categories of subjects investigated, significant enhancement of IL-2 production and improved proliferation of CD4 T helper cells are restricted to viremic individuals. In peripheral blood mononuclear cells (PBMCs), this IL-10 is produced primarily by CD14(+) monocytes, but ...
It has been reported that a growing and heterogeneous group of regulatory cell modulate immune response. In particular, regulation of CD8+ T lymphocyte effector functions is critical for tissue homeostasis and immune tolerance control. Here, we report that the co-expression of CD3 and CD56 molecules identify a novel human regulatory T cell population exerting suppressive activity on proliferation, cytotoxicity and IFN- production of TCR-activated human CD8+ T lymphocytes. Regulatory functions of human circulating CD3+CD56+ T lymphocytes require cell-to-cell contact and are exerted in both autologous and allogeneic conditions. Of note, CD3+CD56+ T cells are reduced and functionally impaired in children affected by Type 1 Diabetes (T1D), at disease onset. Conversely the frequency of this cell subset is increased in patients with prostate cancer. Taken together, our findings reveal that freshly isolated human CD3+CD56+ cells specifically control activation of human CD8+ T lymphocytes. ...
T cells play a dominant role in the pathogenesis of asthma. Costimulation of T cells is necessary to fully activate them. An inducible costimulator (ICOS) of T cells is predominantly expressed on Th2 cells. Therefore, interference of signaling pathways precipitated by ICOS may present new therapeutic options for Th2 dominated diseases such as asthma. However, these signaling pathways are poorly characterized in vitro and in vivo. Human primary CD4+ T cells from blood were activated by beads with defined combinations of surface receptor stimulating antibodies and costimulatory receptor ligands. Real-time RT-PCR was used for measuring the production of cytokines from activated T cells. Activation of mitogen activated protein kinase (MAPK) signaling pathways leading to cytokine synthesis were investigated by western blot analysis and by specific inhibitors. The effect of inhibitors in vivo was tested in a murine asthma model of late phase eosinophilia. Lung inflammation was assessed by differential cell
We measured the frequency of clonally expanded and persistent T cells recognizing the immunodominant MBPp8599 epitope in subjects with typical relapsing remitting MS. Single T cells expressing mRNA transcripts encoding TCR-α and -β chains found in T cell clones previously isolated from these subjects recognizing the MBPp85-99 epitope were examined. In contrast to frequencies of 1 in 105 to 106 as measured by LDA, estimates of the T cell frequencies expressing TCR chain transcripts associated with MBPp8599 recognition were as high as 1 in 300.. In retrospect, the high frequencies of MBPp85-99-reactive T cells with presumed chronic stimulation is perhaps not surprising. Subjects with HTLV-I and HIV infection have high frequencies of virus reactive T cells as measured ex vivo in peripheral blood using direct cytotoxicity assays (25- 27). In contrast, the LDA analysis of CTL frequencies in HIV-infected patients which requires T cell expansion leads to an 100-fold underestimate of CTL effector ...
Activation of CD4+ T cells occurs through the simultaneous engagement of the T-cell receptor and a co-stimulatory molecule (like CD28, or ICOS) on the T cell by the major histocompatibility complex (MHCII) peptide and co-stimulatory molecules on the APC. Both are required for production of an effective immune response; in the absence of co-stimulation, T cell receptor signalling alone results in anergy. The signalling pathways downstream from co-stimulatory molecules usually engages the PI3K pathway generating PIP3 at the plasma membrane and recruiting PH domain containing signaling molecules like PDK1 that are essential for the activation of PKCθ, and eventual IL-2 production. Optimal CD8+ T cell response relies on CD4+ signalling.[33] CD4+ cells are useful in the initial antigenic activation of naïve CD8 T cells, and sustaining memory CD8+ T cells in the aftermath of an acute infection. Therefore, activation of CD4+ T cells can be beneficial to the action of CD8+ T cells.[34][35][36]. The ...
Activation of CD4+ T cells occurs through the simultaneous engagement of the T-cell receptor and a co-stimulatory molecule (like CD28, or ICOS) on the T cell by the major histocompatibility complex (MHCII) peptide and co-stimulatory molecules on the APC. Both are required for production of an effective immune response; in the absence of co-stimulation, T cell receptor signalling alone results in anergy. The signalling pathways downstream from co-stimulatory molecules usually engages the PI3K pathway generating PIP3 at the plasma membrane and recruiting PH domain containing signaling molecules like PDK1 that are essential for the activation of PKC-θ, and eventual IL-2 production. Optimal CD8+ T cell response relies on CD4+ signalling.[33] CD4+ cells are useful in the initial antigenic activation of naïve CD8 T cells, and sustaining memory CD8+ T cells in the aftermath of an acute infection. Therefore, activation of CD4+ T cells can be beneficial to the action of CD8+ T cells.[34][35][36] The ...
Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors - Search Results - PubMed
Mark, there has been a number of discussions on this list regarding RA/RO... Im not going to rehash those discussions, since I dont want to bore everyone else. Go to the archives and read over the material -- it includes references. But once again, CD45RA+ cells are BOTH naive AND memory. You CANNOT use RA and/or RO to identify naive T cells without an additional marker such as CD62L, CD11a, CD27. As for Double-positive, it depends on how you define positive. Bright (true) RA+RO+ double positives are very rare in peripheral blood but common in active tissues (like tonsil). Cells positive for one and dull for the other are normal resting memory T cells. There are no double-negative cells that are viable. Percentages in the peripheral blood are meaningless for the simple reason that RA+ cells are a heterogeneous mixture of naive & memory. Especially the CD8s, where anywhere between 20 and 80% of RA+ cells can be memory. (In CD4, most (95%) are naive; however, in many disease states ...
The total number of T cells present in the antigen-specific pool at the site of priming is determined by three cell-intrinsic parameters: the proportion of T cells entering into the proliferating pool, their cycle activity, and their survival. In accordance with published data (2), we found that CD28 increased cell cycle entry as well as activity. Early studies also report that CD28 promotes the survival of activated T cells (3). From measuring [3H]thymidine incorporation at different time points after TCR stimulation, it was concluded that this prosurvival effect came into play at a late time point and in fact sustained the proliferative response. However, we demonstrate that CD28−/− T cells die in much higher frequency than wild-type T cells when making the transition from G1 to S for the first time. CD28 strongly promotes cell survival at this point, thus greatly increasing the proportion of cells taking part in further divisions. The prosurvival effect of CD28 has been attributed to ...
Systemic CD4+ T Cell Loss Resulting from Intravaginal HIV-1 Infection in Humanized BLT Mice(A) Comparison of the levels of CD4+ or CD8+ human T cells in the ind
Recently, growing evidences suggest that CD8+CD122+PD-1+ T cells are also a subset of Treg cells, which have more ability to suppress the allograft rejection and undergo faster homeostatic proliferation than conventional CD4+CD25+Foxp3+ Treg cells (31, 32, 40). subsets, and display enhanced functionality in terms of degranulation and cytokine production on a per-cell basis. Additionally, we have identified the novel splice junctions that use a high ratio of the non-canonical splicing motif GC-AG and found that AS is not a major contributor to the gene expression-level changes between paired pCD8 and dCD8 T cells. Together, our findings not only provide a comprehensive framework of the transcriptional and AS landscapes but also reveal the functional feature of human PF-05175157 dCD8 T cells, which are of great importance in understanding the biology of these cells and the physiology of human healthy pregnancy. mRNA transcript abundance (14, 15). As an ubiquitous and crucial mechanism to regulate ...
T cells play pivotal roles in shaping host immune responses in infectious diseases, autoimmunity and cancer. The activation of T cells requires immune and growth factor-derived signals. However, alterations in nutrients and metabolic signals tune T cell responses by impinging upon T cell fates and immune functions. In this review, we summarize how key nutrients, including glucose, amino acids and lipids, and their sensors and transporters shape T cell responses. We also briefly discuss regulation of T cell responses by oxygen and energy sensing mechanisms.
Tissue-resident memory T cells (T|sub|RM|/sub| cells) are crucial mediators of adaptive immunity in nonlymphoid tissues. However, the functional heterogeneity and pathogenic roles of CD4|sup|+|/sup| T|sub|RM|/sub| cells that reside within chronic inflammatory lesions remain unknown. We found that CD …
The immune system has evolved to fend off challenges from a wide array of pathogens while maintaining tolerance to self-antigens and benign environmental antigens. CD4 helper T cells are critical in regulating these processes with different subsets of CD4 T cells responsible for regulating different facets of the immune system. T helper 1 (Th1) cells, which contribute to antiviral immunity, and T helper 2 (Th2) cells, which contribute to antihelminth immunity and allergy, were the first CD4 T cell subsets to be discovered. Recently a number of new subsets have been discovered. Here we review what is known about CD4 T cell subsets with particular focus on neonatal immunity. ...
A major challenge in the HIV field has been to understand why the strength of virus-specific CD8 T cell responses has no relationship to viral load, and yet CD8 depletion studies indicate that these cells are critical for immune control. And a major challenge in the field of immunology in general has been the rapid translation of advances in murine models to humans. In late 2005, through a telephone conversation with Rafi Ahmed, we became aware of yet unpublished data in the mouse model of chronic infection. His laboratory had shown that in mice persistently infected with LCMV, T cells up-regulate a surface molecule termed PD-1, for programmed death-1, a negative immunoregulatory molecule that turned off CD8 T cell function. The potential parallels with HIV were immediately obvious to us-perhaps persistent exposure to HIV was having a similar impact on CD8 T cell function in humans, and perhaps similar immune regulation was rendering CD4 T cells exhausted as well.. We immediately formed a ...
Several immune cell subtypes were analyzed in HPV16-associated cancers by Chantal Duurland, PhD (Leiden University Medical Center) and colleagues. HPV+ patients have increased survival compared to HPV- patients, thus the role of the immune response to these cancers should be better elucidated. High levels of CD4+CD161+ infiltrating T cells have been found in HPV+ tumors; therefore, the authors used a multi-level approach to understanding the importance of this unique subset of CD4+ T cells in the HPV+ tumor microenvironment. The authors also described a population of CD14-CD33-CD163+ cells, which were identified as dendritic cells (DCs). This subset of DCs was found to associate with strong T cell infiltrates and improved patient survival, similar to CD4+CD161+ T cells. Thus, there was an effort to understand the crosstalk of these two immune subsets in HPV+ disease. Further analyses demonstrated that activated CD163+ DCs generated higher levels of both IL-12 and IL-18 compared to their CD163- ...
CD160 is an Ig-like glycoprotein expressed by the majority of circulating natural killer cells and γδ T cells. Whether CD160 could regulate CD8+
ECIA™ Intracellular cytokine staining assay is utilized to detect the antigen-specific T cell responses, immunogenic analysis, epitope discovery at a single cell level for both clinical studies and scientific researches.
Depending on the receptors on the surface of the macrophage, a T cell can distinguish the hepatitis virus from that of flu, without ever having seen before. T cells that belong to this category are called naive T cells. Naive T cells are the fresh troops, the virgin field of battle, called to intervene when we get sick we contract a new disease or a new infection. There are even T cells can recognize antigens produced in artificial laboratory that the human body has never encountered in millions of years of evolution. The type of T cell that recognizes the antigen is called the CD4 cell (also called CD4 helper T-cell or lymphocyte), one of the same name situated on its surface called receptors, in fact, CD4 receptor. Although not usually the cells that kill the invader, CD4 cells are the most important of the entire immune system. This is because their main function is to send signals that direct and mobilize other troops into battle. We should think of T-helper cells as troop commanders or ...
Unlike HIV-1-infected people, most HIV-2-infected subjects maintain a healthy CD4+ T cell count and a strong HIV-specific CD4+ T cell response. To define the cellular immunological correlates of good prognosis in HIV-2 infection, we conducted a cross-sectional study of HIV Gag-specific T cell function in HIV-1- and HIV-2-infected Gambians. Using cytokine flow cytometry and lymphoproliferation assays, we show that HIV-specific CD4+ T cells from HIV-2-infected individuals maintained proliferative capacity, were not terminally differentiated (CD57-), and more frequently produced IFN-gamma or IL-2 than CD4+ T cells from HIV-1-infected donors. Polyfunctional (IFN-gamma+/IL-2+) HIV-specific CD4+ T cells were found exclusively in HIV-2+ donors. The disparity in CD4+ T cell responses between asymptomatic HIV-1- and HIV-2-infected subjects was not associated with differences in the proliferative capacity of HIV-specific CD8+ T cells. This study demonstrates that HIV-2-infected donors have a well-preserved and
CD248 (endosialin) is a transmembrane glycoprotein that is dynamically expressed on pericytes and fibroblasts during tissue development, tumour neovascularization and inflammation. Its role in tissue remodelling is associated with increased stromal cell proliferation and migration. We show that CD248 is also uniquely expressed by human, but not mouse (C57BL/6), CD8(+) naive T cells. CD248 is found only on CD8(+) CCR7(+) CD11a(low) naive T cells and on CD8 single-positive T cells in the thymus. Transfection of the CD248 negative T-cell line MOLT-4 with CD248 cDNA surprisingly reduced cell proliferation. Knock-down of CD248 on naive CD8 T cells increased cell proliferation. These data demonstrate opposing functions for CD248 on haematopoietic (CD8(+)) versus stromal cells and suggests that CD248 helps to maintain naive CD8(+) human T cells in a quiescent state.
The primary goal of this study was to resolve the uncertainty about whether HESNs make T cell responses to HIV-1. We compared the frequencies of HIV-1-specific T cell responses over time between HESN and HUSN groups in a powered, blind study with independent data analysis. In these donors, no T cell responses were detectable without culture, except, notably, in an HESN participant who was homozygous for CCR5Δ32 and therefore genetically resistant to HIV-1 infection (18, 46). Using the more sensitive cultured ELISpot assay, T cell responses were found in both HESNs and HUSNs. Significant differences were found in the frequencies of T cell responses over time, with HESNs more likely to have positive T cell responses than HUSNs. HESNs more often maintained HIV-1-specific T cell responses across visits than HUSNs. Also, among positive responders, T cell responses were of significantly higher magnitude in HESNs than in HUSNs. Given that the cultured ELISpot assay expands antigen-specific cells ...
BACKGROUND: High levels of ex vivo CD4 T-cell death and the accumulation of highly differentiated and/or immunosenescent T cells have been associated with poor CD4 T-cell recovery in treated HIV-infected individuals. However, the relationship between cell death and T-cell differentiation is still unclear. METHODS: We have analyzed cell death, immunosenescence and differentiation parameters in HAART-treated subjects (VL |50 copies/mL for more than 2 years) with CD4 T-cell count |350 cells/μL (immunodiscordant, n = 23) or |400 cells/μL (immunoconcordant, n = 33). We included 11 healthy individuals as reference. RESULTS: As expected, suboptimal CD4 T-cell recovery was associated with low frequencies of naïve cells, high frequencies of transitional and effector memory cells and a subsequent low ratio of central/transitional memory cells in the CD4 compartment. These alterations correlated with spontaneous CD4 T-cell death. A deeper analysis of cell death in CD4 T-cell subsets showed increased cell death
BACKGROUND: The relative immunogenicity of human immunodeficiency virus type 1 (HIV-1) proteins for CD8+ and CD4+ cell responses has not been defined. METHODS: HIV-1-specific T cell responses were evaluated in 65 chronically HIV-1-infected untreated subjects by interferon- gamma flow cytometry with peptides spanning the clade C consensus sequence. RESULTS: The magnitude of HIV-1-specific CD8+ T cell responses correlated significantly with CD4+ cell responses, but the percentage of CD8+ T cells directed against HIV-1 (median, 2.76%) was always greater than that of CD4+ cells (median, 0.24%). Although CD8+ T cell responses were equally distributed among Gag, Pol, and the regulatory and accessory proteins, Gag was the dominant target for CD4+ cell responses. There was no consistent relationship between virus-specific CD8+ or CD4+ cell response and viral load. However, the median viral load in subjects in whom Gag was the dominant CD8+ T cell target was significantly lower than that in subjects in whom non
Methods and Results: High-purity sorted CD4+ T cells from ACS patients were treated with a panel of cytokines (TNF-α, IL-1β, IL-6, IL-7, IL-15), and effects on the number, phenotype and function of CD28null T cells were analysed and compared to the control counterpart CD28+ T cell subset. IL-7 and IL-15 induced expansion of CD28null T cells from ACS patients, while inflammatory cytokines TNF-α, IL-1β and IL-6 did not. The mechanisms underlying CD28null T cell expansion by IL-7/IL-15 were preferential activation and proliferation of CD28null T cells compared to control CD28+ T cells. Additionally, IL-7/IL-15 markedly augmented CD28null T cell cytotoxic function and interferon-γ production. Further mechanistic analyses revealed differences in baseline expression of component chains of IL-7/IL-15 receptors (CD127 and CD122) and increased baseline STAT5 phosphorylation in CD28null T cells from ACS patients compared to the control CD28+ T cell subset. Notably, we demonstrate that CD28null T cell ...
The mechanisms underlying the regulation of immune activation and immune exhaustion of T cells are unclear. Tregs have been investigated in HIV-1-infected subjects with conflicting results. Our data suggest that exhausted T cells are not only associated with hyperactivated T cells but also with reduced numbers of Tregs. When we determined the CD4+CD25bright FoxP3+ Treg population in proportion to CD4+CD25bright FoxP3 negative non-Treg activated CD4 T cells, we noted that the proportions were altered in favor of the non-Treg-activated CD4 T cells in HIV-positive subjects. In this analysis, however, the changes observed in Treg frequency could have simply been a consequence of changes in activated CD4+ T-cell frequency. On the other hand, the percentage of Tregs in the total CD4+ T-cell population of the viremic patients was also significantly lower as compared with aviremic patients and to healthy controls. As activated CD8 T cells were also clearly higher in viremic patients, this provides ...
Despite progress toward understanding the correlates of protective T cell immunity in HIV infection, the optimal approach to Ag delivery by vaccination remains uncertain. We characterized two immunodominant CD8 T cell populations generated in response to immunization of BALB/c mice with a replication-deficient adenovirus serotype 5 vector expressing the HIV-derived Gag and Pol proteins at equivalent levels. The Gag-AI9/H-2Kd epitope elicited high-avidity CD8 T cell populations with architecturally diverse clonotypic repertoires that displayed potent lytic activity in vivo. In contrast, the Pol-LI9/H-2Dd epitope elicited motif-constrained CD8 T cell repertoires that displayed lower levels of physical avidity and lytic activity despite equivalent measures of overall clonality. Although low-dose vaccination enhanced the functional profiles of both epitope-specific CD8 T cell populations, greater polyfunctionality was apparent within the Pol-LI9/H-2Dd specificity. Higher proportions of central ...
The initial idea that high amounts of cytopathic virus produced everyday can drive high CD4+ T cell production seemed logical and explained the progressive CD4+ T cell depletion observed in HIV-infected subjects. It was hypothesized that the CD4+ T lymphocyte production was increased up to 70-fold in HIV-infected subjects. Determination of the CD4+ T cell production was based on the kinetics of CD4+ T cell recovery following initiation of highly-active antiretroviral therapy (HAART). However, this analysis was limited by: (1) the assumption that blood CD4+ T cells are representative of the lymph node T cells; and (2) the lack of estimates of CD4+ T lymphocyte turnover in healthy HIV-negative subjects. Several immunologists have expressed caution regarding the assumptions used in modeling CD4+ T cell dynamics. Recent findings clearly show that blood is not representative of lymphoid tissues. Indeed, when blood and lymph node compartments are considered together, we find that HIV -infected ...
The peripheral naive T-cell pool is generally thought to consist of a subpopulation of recent thymic emigrants (RTE) and a subpopulation of mature naive (MN) T cells with different dynamics. Thymus transplantation and adoptive transfer studies in mice have provided contradicting results, with some studies suggesting that RTE are relatively short-lived cells, while another study suggested that RTE have a survival advantage. We here estimate the death rates of RTE and MN T cells by performing both thymus transplantations and deuterium labeling experiments in mice of at least 12 weeks old, an age at which the size of the T-cell pool has stabilized. For CD4+ T cells, we found the total loss rate from the RTE compartment (by death and maturation) to be 4-fold faster than that of MN T cells. We estimate the death rate of CD4+ RTE to be 0.046 per day, which is 3-fold faster than the total loss rate from the MN T-cell compartment. For CD8+ T cells, we found no evidence for kinetic differences between RTE and MN
Autoreactive CD8 T cells play a central role in the destruction of pancreatic islet β-cells that leads to type 1 diabetes, yet the key features of this immune-mediated process remain poorly defined. In this study, we combined high-definition polychromatic flow cytometry with ultrasensitive peptide-human leukocyte antigen class I tetramer staining to quantify and characterize β-cell-specific CD8 T cell populations in patients with recent-onset type 1 diabetes and healthy control subjects. Remarkably, we found that β-cell-specific CD8 T cell frequencies in peripheral blood were similar between subject groups. In contrast to healthy control subjects, however, patients with newly diagnosed type 1 diabetes displayed hallmarks of antigen-driven expansion uniquely within the β-cell-specific CD8 T cell compartment. Molecular analysis of selected β-cell-specific CD8 T cell populations further revealed highly skewed oligoclonal T cell receptor repertoires comprising exclusively private clonotypes. ...
TY - JOUR. T1 - Expression of the costimulatory receptor CD30 is regulated by both CD28 and cytokines. AU - Gilffillan, Molly C.. AU - Noel, Patricia J.. AU - Podack, Eckhard R.. AU - Reiner, Steven L.. AU - Thompson, Craig B.. PY - 1998/3/1. Y1 - 1998/3/1. N2 - Costimulation was originally defined and characterized during primary T cell activation. The signaling events that regulate subsequent antigen encounters by T cells are less well defined. In this study we examined the role of CD30 in T cell activation and defined factors that regulate expression of CD30 on T cells. We demonstrate that CD30 expression is restricted to activated T cells and regulated by CD28 signal transduction. In contrast to CD28-expressing TCR Tg cells, CD28-deficient TCR Tg cells did not express CD30 when cultured with peptide and APCs. However, rIL-4 reconstituted CD30 expression on CD28-deficient TCR Tg cells. Blockade of CD28 interactions or depletion of IL-4 inhibited the induction of CD30, suggesting that both ...
Interleukin-15 (IL-15) is an inflammatory cytokine whose role in autoimmune diseases has not been fully elucidated. Th17 cells have been shown to play critical roles in experimental autoimmune encephalomyelitis (EAE) models. In this study, we demonstrate that blockade of IL-15 signaling by TMβ-1 mAb treatment aggravated EAE severity. The key mechanism was not NK-cell depletion but depletion of CD8+ CD122+ T cells. Adoptive transfer of exogenous CD8+ CD122+ T cells to TMβ-1-treated mice rescued animals from severe disease. Moreover, transfer of pre-activated CD8+CD122+ T cells prevented EAE development and significantly reduced IL-17 secretion. Naïve effector CD4+ CD25- T cells cultured with either CD8+CD122+ T cells from wild-type mice or IL-15 transgenic mice displayed lower frequencies of IL-17A production with lower amounts of IL-17 in the supernatants when compared with production by effector CD4+ CD25- T cells cultured alone. Addition of a neutralizing antibody to IL-10 led to recovery ...
Hyperactivation of T cells, particularly of CD8(+) T cells, is a hallmark of chronic HIV 1 (HIV-1) infection. Little is known about the antigenic specificities and the mechanisms by which HIV-1 causes activation of CD8(+) T cells during chronic infection. We report that CD8(+) T cells were activated during in vivo HIV-1 replication irrespective of their Ag specificity. Cytokines present during untreated HIV-1 infection, most prominently IL-15, triggered proliferation and expression of activation markers in CD8(+) T cells, but not CD4(+) T cells, in the absence of TCR stimulation. Moreover, LPS or HIV-1-activated dendritic cells (DCs) stimulated CD8(+) T cells in an IL-15-dependent but Ag-independent manner, and IL-15 expression was highly increased in DCs isolated from viremic HIV-1 patients, suggesting that CD8(+) T cells are activated by inflammatory cytokines in untreated HIV-1 patients independent of Ag specificity. This finding contrasts with CD4(+) T cells whose in vivo activation seems ...
Interleukin-12 (IL-12) induces differentiation of T helper 1 (Th1) cells, primarily through its ability to prime T cells for high interferon-gamma (IFN-gamma) production. We now report that the presence of IL-12 during the first several days of in vitro clonal expansion in limiting dilution cultures of polyclonally stimulated human peripheral blood CD4+ and CD8+ T cells also induces stable priming for high IL-10 production. This effect was demonstrated with T cells from both healthy donors and HIV+ patients. Priming for IL-4 production, which requires IL-4, was maximum in cultures containing both IL-12 and IL-4. IL-4 modestly inhibited the IL-12-induced priming for IFN-gamma, but almost completely suppressed the priming for IL-10 production. A proportion of the clones generated from memory CD45RO+ cells, but not those generated from naive CD45RO- CD4+ T cells, produced some combinations of IFN-gamma, IL-10, and IL-4 even in the absence of IL-12 and IL-4, suggesting in vivo cytokine priming; ...
The function of CD8 cells in the human body is to kill infected target cells, such as HIV infected cells. Recent data suggest that intravenous administration of HIV-specific CD8 cells is safe, augments host immunity, and mediates a dramatic reduction in circulating HIV-infected CD4 cells. However, the observed antiviral effects are transient, and HIV infected CD4 cells re-emerge as the number of self CD8 cells declines. Augmenting CD8 cell response to HIV by immunotherapy with CD8 cells may be a useful addition to drug therapy if the infused CD8 cells can survive long-term in vivo. Administration of interleukin-2 (also known as aldesleukin or IL-2), a naturally occurring cytokine, has been proposed as a way to maintain the number of CD8 cells. This study will evaluate the safety and efficacy of immunotherapy with HIV-specific CD8 cells in HIV infected patients. Additionally, this study will determine if aldesleukin injections improve the persistence of self CD8 transplants and the duration of ...
The function of CD8 cells in the human body is to kill infected target cells, such as HIV infected cells. Recent data suggest that intravenous administration of HIV-specific CD8 cells is safe, augments host immunity, and mediates a dramatic reduction in circulating HIV-infected CD4 cells. However, the observed antiviral effects are transient, and HIV infected CD4 cells re-emerge as the number of self CD8 cells declines. Augmenting CD8 cell response to HIV by immunotherapy with CD8 cells may be a useful addition to drug therapy if the infused CD8 cells can survive long-term in vivo. Administration of interleukin-2 (also known as aldesleukin or IL-2), a naturally occurring cytokine, has been proposed as a way to maintain the number of CD8 cells. This study will evaluate the safety and efficacy of immunotherapy with HIV-specific CD8 cells in HIV infected patients. Additionally, this study will determine if aldesleukin injections improve the persistence of self CD8 transplants and the duration of ...
TY - JOUR. T1 - Counter-regulation of regulatory T cells by autoreactive CD8 + T cells in rheumatoid arthritis. AU - Cammarata, Ilenia. AU - Martire, Carmela. AU - Citro, Alessandra. AU - Raimondo, Domenico. AU - Fruci, Doriana. AU - Melaiu, Ombretta. AU - DOria, Valentina. AU - Carone, Chiara. AU - Peruzzi, Giovanna. AU - Cerboni, Cristina. AU - Santoni, Angela. AU - Sidney, John. AU - Sette, Alessandro. AU - Paroli, Marino. AU - Caccavale, Rosalba. AU - Milanetti, Edoardo. AU - Riminucci, Mara. AU - Timperi, Eleonora. AU - Piconese, Silvia. AU - Manzo, Antonio. AU - Montecucco, Carlomaurizio. AU - Scrivo, Rossana. AU - Valesini, Guido. AU - Cariani, Elisabetta. AU - Barnaba, Vincenzo. PY - 2019/1/1. Y1 - 2019/1/1. N2 - The mechanisms whereby autoreactive T cells escape peripheral tolerance establishing thus autoimmune diseases in humans remain an unresolved question. Here, we demonstrate that autoreactive polyfunctional CD8 + T cells recognizing self-antigens (i.e., vimentin, actin ...
CD8hiCD57+ T cells have previously been described as effector memory T cells with minimal expansion capacity and high susceptibility to activation-induced cell death. In contrast, we demonstrate here that CD8hiCD57+ T cells are capable of rapid expansion using multiple techniques including [3H]thymidine uptake, flow cytometric bead-based enumeration and standard haemocytometer counting. Previous reports can be explained by marked inhibition of activation-induced expansion and increased 7-amino-actinomycin D uptake by CD8hiCD57+ T cells following treatment with CFSE, a dye previously used to measure their proliferation, combined with specific media requirements for the growth of this cell subset. The ability of CD8hiCD57+ T cells to further differentiate is highlighted by a distinct cytokine profile late after activation that includes the unexpected release of high levels of interleukin 5. These data indicate that CD8hiCD57+ T cells should not be considered as end-stage effector T cells ...
TY - JOUR. T1 - Failure to suppress the expansion of the activated CD4 T cell population in interferon γ-deficient mice leads to exacerbation of experimental autoimnaune encephalomyelitis. AU - Chu, Cong Qiu. AU - Wittmer, Susan. AU - Dalton, Dyana K.. PY - 2000/7/3. Y1 - 2000/7/3. N2 - Mice deficient in interferon (IFN)-γ or IFN-γ receptor develop progressive and fatal experimental autoimmune encephalomyelitis (EAE). We demonstrate that CD4 T cells lacking IFN-γ production were required to passively transfer EAE, indicating that they were disease-mediating cells in IFN-γ knockout (KO) mice. IFN-γ KO mice accumulated 10-16-fold more activated CD4 T cells (CD4+CD44(hi)) than wild-type mice in the central nervous system during EAE. CD4+CD44(hi) T cells in the spleen and central nervous system of IFN-γ KO mice during EAE showed markedly increased in vivo proliferation and significantly decreased ex vivo apoptosis compared with those of wild-type mice. IFN-ψ KO CD4+CD44(hi) T cells ...
The occurrence of massive CD4+ T cell depletion is one of the most prominent characteristics of human immunodeficiency virus type 1 (HIV-1) infection during acute phase, resulting in unrestorable destruction to the immune system. The infected host undergoes an asymptomatic period lasting several years with low viral load and ostensibly healthy status, which is presumably due to virus-specific adaptive immune responses. In the absence of therapy, an overwhelming majority of cases develop to AIDS within 8-10 years of latent infection. In this review, we discuss the roles in AIDS pathogenesis played by massive CD4+ T lymphocytes depletion in gut-associated lymphoid tissue (GALT) during acute infection and abnormal immune activation emerging in the later part of chronic phase.
Fingerprint Dive into the research topics of Recognition of naturally processed and ovarian cancer reactive CD8 ,sup,+,/sup, T cell epitopes within a promiscuous HLA class II T-helper region of NY-ESO-1. Together they form a unique fingerprint. ...
In the absence of foreign antigen, peripheral naive T cells continuously recirculate between different lymphoid organs, in which they interact frequently and shortly with self. We and others have shown that such interactions are required for the long-term survival of naïve T cells. In addition, these TCR/MHC interactions and the resulting associated signaling increase quantitatively T-cell responsiveness towards foreign antigens and influence their function and/or differentiation into effector or memory cells in response to stimulation. Our project is based on our recent data showing that peripheral ab and gd T cells can be subdivided into various subsets according to Ly-6C expression. Interestingly, in CD4 ab T cells, Ly-6C expression inversely correlates with the ability of these cells to interact with self, defining Ly-6C as a new sensor of T cell self-reactivity. In parallel, we are exploring the regulation of T-cell self-reactivity in the context of cancer. Indeed, T cells specific for ...
Zhang Y, Feng ZP, Naselli G, Bell F, Wettenhall J, Auyeung P, Ellis JA, Ponsonby AL, Speed TP, Chong MM, Harrison LC. MicroRNAs in CD4(+) T cell subsets are markers of disease risk and T cell dysfunction in individuals at risk for type 1 diabetes. Journal of autoimmunity 68 : 52 - 61(2016) PubMed (Grant IDs: 637338, 1004541, 1037321, 1026349 ...
The origin of CD4+ T cells reappearing in the blood following antiretroviral therapy in human immunodeficiency virus type-1 (HIV-1) infection is still controversial. Here we show, using mathematical modeling, that redistribution of T cells to the blood can explain the striking correlation between the initial CD4+ and CD8+ memory T-cell ... read more repopulation and the observation that 3 weeks after the start of treatment memory CD4+ T-cell numbers reach a plateau. The increase in CD4+ T cells following therapy most likely is a composite of initial redistribution, accompanied by a continuous slow repopulation with newly produced naive T cells. show less ...
Multiple viral and host factors determine the variability in HIV-1 disease progression [17, 23-26]. Cellular tropism and receptor/co-receptor usage for viral entry are major factors influencing HIV pathogenesis. Despite extensive research, the exact mechanism of how those factors contribute to the gradual loss of CD4 T cells is still enigmatic. Bystander CD4 T cell death plays a major contribution towards AIDS progression. A recent report has revealed a mechanism for HIV-induced CD4 T cell depletion, which involves abortive non-productive HIV infection in resting CD4 T cells, followed by IFI16 activation and caspase-1 dependent pyroptosis [27-29]. Besides the abortive RT products in non-productively infected resting cells, several HIV-1 proteins have also been reported to contribute to the depletion of bystander (uninfected and non-productively infected) CD4 T cells, including the Env [4, 5, 17, 19], Vpr [30], Nef [31, 32] and Tat [33]. The Env protein is of specific interest in mediating AIDS ...
T cell responses play an important role in the outcome of HBV and HCV infection, e.g. viral elimination versus persistence. However, multiple mechanisms can lead to the failure of the virus-specific T cell response. These mechanisms include primary T cell failure, T cell exhaustion, the emergence of viral escape mutants, as well as T cell dysfunction. Furthermore, genetic factors such as the individual HLA allele background play an important role in the outcome of infection. Once viral persistence has been established, HBV or HCV infection can progress to liver fibrosis and cirrhosis with an enhanced risk for HCC. Tumor-specific T cells (e.g. AFP-specific T cells) are thought to contribute to cancer control.. The focus of our group is the identification and characterization of virus-specific CD4+ and CD8+ T cell responses during acute and chronic HBV and HCV infection with a special focus on intrahepatic T cell responses as well as the mechanisms of viral persistence (e.g., viral escape, T cell ...
In this study, we documented that local cryo-thermal therapy generated a stronger systematic antitumor immune response than RFA and a long-lasting antitumor immunity that protected against tumor rechallenge. At the same time, a systemic antigen-specific T-cell immune response induced via local cryo-thermal therapy was revealed. Although the survival rate between RFA and cryo-thermal therapy was not statistically significant, the long-term immunity against tumor challenge elicited by two treatments was different. In vitro studies showed that the antigen-specific CD8+ T-cell response was induced by both cryo-thermal therapy and RFA, but the strong neoantigen-specific CD4+ T-cell response was only induced by cryo-thermal therapy. Moreover, we demonstrated that the cryo-thermal therapy-induced strong antitumor immune response was mainly mediated by CD4+ T-cells, particularly neoantigen-specific CD4+ T-cells, which are the major contributors to the cryo-thermal therapy-induced antitumor immune ...
TY - JOUR. T1 - Comparable T helper 1 (Th1) and CD8 T-cell immunity by targeting HIV gag p24 to CD8 dendritic cells within antibodies to Langerin, DEC205, and Clec9A. AU - Idoyaga, Juliana. AU - Lubkin, Ashira. AU - Fiorese, Christopher. AU - Lahoud, Mireille H.. AU - Caminschi, Irina. AU - Huang, Yaoxing. AU - Rodriguez, Anthony. AU - Clausen, Björn E.. AU - Park, Chae Gyu. AU - Trumpfheller, Christine. AU - Steinmana, Ralph M.. PY - 2011/2/8. Y1 - 2011/2/8. N2 - Improved protein-based vaccines should facilitate the goal of effective vaccines against HIV and other pathogens. With respect to T cells, the efficiency of immunization, or immunogenicity, is improved by targeting vaccine proteins to maturing dendritic cells (DCs) within mAbs to DC receptors. Here, we compared the capacity of Langerin/CD207, DEC205/CD205, and Clec9A receptors, each expressed on the CD8+ DC subset in mice, to bring about immunization of microbial-specific T cells from the polyclonal repertoire, using HIV gag-p24 ...
Microbiota-reactive CD4+ T memory (TM) cells are generated during intestinal infections and inflammation, and can revert to pathogenic CD4+ T effector (TE) cells, resulting in chronicity of inflammatory bowel disease (IBD). Unlike TE cells, TM cells have a low rate of metabolism unless they are activated by reencountering cognate antigen. Here, we show that the combination of cell activation and metabolic checkpoint inhibition (CAMCI), by targeting key metabolic regulators mTORC and AMPK, resulted in cell death and anergy, but enhanced the induction of the regulatory subset. Parenteral application of this treatment with a synthetic peptide containing multiple flagellin T cell epitopes (MEP1) and metabolic inhibition successfully prevented the development of CD4+ T cell-driven colitis. Microbiota-specific CD4+ T cells, especially the pathogenic TE subsets, were decreased 10-fold in the intestinal lamina propria. Furthermore, using the CAMCI strategy, we were able to prevent antigen-specific TM ...
In the present study, we demonstrate a novel mechanism by which CD8+ T cells contribute to atherogenesis through modulation of medullar monopoiesis and circulating Ly6Chi monocyte levels, thereby indirectly controlling macrophage accumulation within lesions.. Previous studies addressing the role of CD8+ T cells in atherogenesis have mostly used genetically engineered mouse models of CD8+ T-cell deficiency with contradictory results,17,18 which may be because of compensatory mechanisms in these mice. We circumvented this hurdle by treating Ldlr−/− mice with an anti-CD8α monoclonal antibody, which efficiently depleted CD8+ T cells while not altering DCs levels, including CD8α+ DCs, and functionality of splenic CD11c+ DCs, as well as leaving CD4+ T cell numbers, activation and polarization untouched, thus confirming the specificity of our depletion strategy.. CD8+ T-cell depletion with the anti-CD8α antibody entailed a significant decrease in atherosclerotic lesion formation in the aortic ...
The human brain is an important site of HIV replication and persistence during antiretroviral therapy (ART). Direct evaluation of HIV infection in the brains of otherwise healthy individuals is not feasible; therefore, we performed a large-scale study of bone marrow/liver/thymus (BLT) humanized mice as an in vivo model to study HIV infection in the brain. Human immune cells, including CD4+ T cells and macrophages, were present throughout the BLT mouse brain. HIV DNA, HIV RNA, and/or p24+ cells were observed in the brains of HIV-infected animals, regardless of the HIV isolate used. HIV infection resulted in decreased numbers of CD4+ T cells, increased numbers of CD8+ T cells, and a decreased CD4+/CD8+ T cell ratio in the brain. Using humanized T cell-only mice (ToM), we demonstrated that T cells establish and maintain HIV infection of the brain in the complete absence of human myeloid cells. HIV infection of ToM resulted in CD4+ T cell depletion and a reduced CD4+/CD8+ T cell ratio. ART ...
The human brain is an important site of HIV replication and persistence during antiretroviral therapy (ART). Direct evaluation of HIV infection in the brains of otherwise healthy individuals is not feasible; therefore, we performed a large-scale study of bone marrow/liver/thymus (BLT) humanized mice as an in vivo model to study HIV infection in the brain. Human immune cells, including CD4+ T cells and macrophages, were present throughout the BLT mouse brain. HIV DNA, HIV RNA, and/or p24+ cells were observed in the brains of HIV-infected animals, regardless of the HIV isolate used. HIV infection resulted in decreased numbers of CD4+ T cells, increased numbers of CD8+ T cells, and a decreased CD4+/CD8+ T cell ratio in the brain. Using humanized T cell-only mice (ToM), we demonstrated that T cells establish and maintain HIV infection of the brain in the complete absence of human myeloid cells. HIV infection of ToM resulted in CD4+ T cell depletion and a reduced CD4+/CD8+ T cell ratio. ART ...