Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques.
(33/13590)
To determine the role of CD8(+) T cells in controlling simian immunodeficiency virus (SIV) replication in vivo, we examined the effect of depleting this cell population using an anti-CD8 monoclonal antibody, OKT8F. There was on average a 99.9% reduction of CD8 cells in peripheral blood in six infected Macaca mulatta treated with OKT8F. The apparent CD8 depletion started 1 h after antibody administration, and low CD8 levels were maintained until day 8. An increase in plasma viremia of one to three orders of magnitude was observed in five of the six macaques. The injection of a control antibody to an infected macaque did not induce a sustained viral load increase, nor did it significantly reduce the number of CD8(+) T cells. These results demonstrate that CD8 cells play a crucial role in suppressing SIV replication in vivo. (+info)
Functional differences between memory and naive CD8 T cells.
(34/13590)
To determine how murine memory and naive T cells differ, we generated large numbers of long-lived memory CD8(+) T cells and compared them to naive cells expressing the same antigen-specific receptor (T cell receptor; TCR). Although both populations expressed similar levels of TCR and CD8, on antigen stimulation in vitro memory T cells down-regulated their TCR faster and more extensively and secreted IFN-gamma and IL-2 faster than naive T cells. Memory cells were also larger, and when freshly isolated from mice they contained perforin and killed target cells without having to be restimulated. They further differed from naive cells in requiring IL-15 for proliferation and in having a greater tendency to undergo apoptosis in vitro. On antigen stimulation in vivo, however, they proliferated more rapidly than naive cells. These findings suggest that, unlike naive T cells, CD8 memory T cells are intrinsically programmed to rapidly express their effector functions in vivo without having to undergo clonal expansion and differentiation. (+info)
Vaccination with a recombinant vaccinia virus encoding a "self" antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4(+) T lymphocytes.
(35/13590)
Many human and mouse tumor antigens are normal, nonmutated tissue differentiation antigens. Consequently, immunization with these "self" antigens could induce autoimmunity. When we tried to induce immune responses to five mouse melanocyte differentiation antigens, gp100, MART-1, tyrosinase, and tyrosinase-related proteins (TRP) 1 and TRP-2, we observed striking depigmentation and melanocyte destruction only in the skin of mice inoculated with a vaccinia virus encoding mouse TRP-1. These mice rejected a lethal challenge of B16 melanoma, indicating the immune response against TRP-1 could destroy both normal and malignant melanocytes. Cytotoxic T lymphocytes specific for TRP-1 could not be detected in depigmented mice, but high titers of IgG anti-TRP-1 antibodies were present. Experiments with knockout mice revealed an absolute dependence on major histocompatibility complex class II, but not major histocompatibility complex class I, for the induction of both vitiligo and tumor protection. Together, these results suggest that the deliberate induction of self-reactivity using a recombinant viral vector can lead to tumor destruction, and that in this model, CD4(+) T lymphocytes are an integral part of this process. Vaccine strategies targeting tissue differentiation antigens may be valuable in cancers arising from nonessential cells and organs such as melanocytes, prostate, testis, breast, and ovary. (+info)
Induction of antitumor immunity by direct intratumoral injection of a recombinant adenovirus vector expressing interleukin-12.
(36/13590)
Direct intratumoral (i.t.) injection of adenoviruses (Ads) expressing specific immunostimulatory cytokines represents an attractive strategy for the clinical implementation of cytokine gene therapy of cancer. Interleukin-12 (IL-12) is a heterodimeric cytokine produced by antigen-presenting cells and promotes a T helper 1-like immune response. We have constructed an Ad vector (AdCMV-mIL-12) containing both chains of the murine IL-12 (mIL-12) gene linked by an internal ribosomal entry site sequence under the transcriptional control of the cytomegalovirus immediate-early gene promoter, which is able to mediate the transient expression of very high levels of biologically active mIL-12 both in vitro and in vivo. An i.t. injection of 4x10(8) plaque-forming units of AdCMV-mIL-12 resulted in a complete regression of day 7 established subcutaneous MC38 murine adenocarcinomas and MCA205 murine fibrosarcomas. Treated animals rejected a subsequent rechallenge with MC38 and MCA205, respectively, demonstrating the induction of long-lasting antitumor immunity. Specific antitumor cytotoxic T lymphocyte reactivity was detected in splenocytes harvested from treated animals. A significant increase in the numbers of both CD4+ and CD8+ T cells in the AdCMV-mIL-12-infected tumors was observed. Ad-mediated IL-12 gene therapy was also associated with measurable serum levels of mIL-12 and profound changes in the composition of splenic lymphocytes. Taken together, these results demonstrate the feasibility and efficacy of delivering IL-12 directly i.t. using a recombinant adenoviral vector. (+info)
Demonstration of bovine CD8+ T-cell responses to foot-and-mouth disease virus.
(37/13590)
The aim of this study was to investigate the importance of cellular immunity in foot-and-mouth disease in cattle, in particular to determine whether a CD8+ T-cell response could be detected, as these cells may play a role in both immunity and virus persistence. As attempts to characterize classical cytotoxic T cells had yielded non-reproducible results, largely due to high backgrounds in control cultures, a proliferation assay was developed that was demonstrated to detect antigen-specific, MHC class I-restricted bovine CD8+ cells responding to foot-and-mouth disease virus (FMDV). Proliferative CD8+ T-cell responses were detected consistently from 10 to 14 days following infection with FMDV and typically lasted 3-4 weeks. The role of CD8+ T cells in control of the disease, in particular their relevance for the establishment of persistence, may now be investigated. (+info)
Phenotypic analysis of lymphocytes and monocytes/macrophages in peripheral blood and bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis.
(38/13590)
BACKGROUND: The granulomatous inflammation in sarcoidosis is driven by the interplay between T cells and macrophages. To gain a better understanding of this process the expression by these cells of cell surface activation markers, co-stimulatory molecules, and adhesion molecules was analysed. METHODS: CD4+ and CD8+ T lymphocytes from peripheral blood (PBL) or bronchoalveolar lavage (BAL) fluid, as well as paired peripheral blood monocytes and alveolar macrophages from 27 patients with sarcoidosis were analysed by flow cytometry. RESULTS: CD26, CD54, CD69, CD95, and gp240 were all overexpressed in T cells from BAL fluid compared with those from PBL in both the CD4+ and CD8+ subsets, while CD57 was overexpressed only in BAL CD4+ cells. In contrast, CD28 tended to be underexpressed in the BAL T cells. Monocyte/macrophage markers included CD11a, CD11b, CD11c, CD14, CD16, CD54, CD71, CD80 and CD86 and HLA class II. CD11a expression in alveolar macrophages (and peripheral blood monocytes) was increased in patients with active disease and correlated positively with the percentage of BAL lymphocytes. Expression of CD80 in macrophages correlated with the BAL CD4/CD8 ratio. CONCLUSIONS: Our data indicate substantial activation of both CD4+ and CD8+ lung T cells in sarcoidosis. There were also increased numbers of BAL lymphocytes whose phenotypic characteristics have earlier been associated with clonally expanded, replicatively senescent cells of the Th1 type. (+info)
Cutting edge: negative selection of immature thymocytes by a few peptide-MHC complexes: differential sensitivity of immature and mature T cells.
(39/13590)
We quantitated the number of peptide-class II MHC complexes required to affect the deletion or activation of 3A9 TCR transgenic thymocytes. Deletion of immature double positive thymocytes was very sensitive, taking place with approximately three peptide-MHC complexes per APC. However, the activation of mature CD4+ thymocytes required 100-fold more complexes per APC. Therefore, a "biochemical margin of safety" exists at the level of the APC. To be activated, autoreactive T cells in peripheral lymphoid tissues require a relatively high level of peptide-MHC complexes. (+info)
Chronic modulation of the TCR repertoire in the lymphoid periphery.
(40/13590)
Using TCR V beta 5 transgenic mice as a model system, we demonstrate that the induction of peripheral tolerance can mold the TCR repertoire throughout adult life. In these mice, three distinct populations of peripheral T cells are affected by chronic selective events in the lymphoid periphery. First, CD4+V beta 5+ T cells are deleted in the lymphoid periphery by superantigens encoded by mouse mammary tumor viruses-8 and -9 in an MHC class II-dependent manner. Second, mature CD8+V beta 5+ T cells transit through a CD8lowV beta 5low deletional intermediate during tolerance induction by a process that depends upon neither mouse mammary tumor virus-encoded superantigens nor MHC class II expression. Third, a population of CD4-CD8-V beta 5+ T cells arises in the lymphoid periphery in an age-dependent manner. We analyzed the TCR V alpha repertoire of each of these cellular compartments in both V beta 5 transgenic and nontransgenic C57BL/6 mice as a function of age. This analysis revealed age-related changes in the expression of V alpha families among different cellular compartments, highlighting the dynamic state of the peripheral immune repertoire. Our work indicates that the chronic processes maintaining peripheral T cell tolerance can dramatically shape the available TCR repertoire. (+info)