Control of immune responses by savenger liver endothelial cells.
(1/459)
The liver appears to be an organ favoring the induction of immune tolerance rather than immunity. Among the hepatic cell populations possibly involved in regulation of immune responses, liver sinusoidal endothelial cells (LSEC) are well suited to fulfill this role. LSEC are resident cells lining the hepatic sinusoidal wall and therefore are in intimate contact with leukocytes passing through the liver. They are equipped with numerous scavenger receptors rendering antigen-uptake in these cells extremely efficient. Antigen processing and MHC-restricted presentation of exogenous antigens for CD4 as well as CD8 T cells occurs equally with high efficiency. Importantly, CD4 and CD8 T cells that engaged in cognate interaction with LSEC have a tolerant phenotype. Thus LSEC contribute an important immune function to the liver: control of the immune response against circulating soluble antigens. (+info)
Immunopathogenic mechanisms in psoriasis.
(2/459)
Psoriasis is a common autoimmune skin disease characterized by T cell-mediated hyperproliferation of keratinocytes. The disease has a strong but complex genetic background with a concordance of approximately 60% in monozygotic twins, and recent linkage and high resolution association studies indicate that HLA-Cw*0602 is itself a major susceptibility allele for psoriasis. Patients carrying this allele have been shown to have different clinical features and earlier age of disease onset, and patients homozygous for this allele have about 2.5 times higher disease risk than heterozygotes. Published data indicate that CD8+ T cells may play a major effector role in psoriasis. Epidermal infiltration of predominantly oligoclonal CD8+ T cells, and probably also of CD4+ T cells in the dermis, is a striking feature of chronic psoriasis lesions, indicating that these cells are responding to specific antigens. We argue that CD4+ T cells are essential for initiating and maintaining the pathogenic process of psoriasis but that cross-primed CD8+ T cells are the main effector cells responding to antigens in the HLA-Cw*0602 binding pocket of keratinocytes. It is further proposed that CD8+ T cells are involved in the control of the Th1 polarization, which is observed in psoriasis lesions, through a complex interplay between CD4+, CD8+ T cells and cross-presenting dendritic cells. It is also suggested that spontaneous remissions or fluctuations in disease activity may be determined by a balance within the lesions between effector and suppressor CD4+ and CD8+ T cells. (+info)
Cellular protein is the source of cross-priming antigen in vivo.
(3/459)
Cross-priming is essential for generating cytotoxic T lymphocytes to viral, tumor, and tissue antigens that are expressed exclusively in parenchymal cells. In this process, the antigen-bearing parenchymal cells must somehow transfer their antigens to bone marrow-derived professional antigen-presenting cells. Although intact proteins, small peptides, or peptide-heat shock protein complexes can all be acquired and presented by antigen-presenting cells, the physiologically relevant form of antigen that is actually transferred from parenchymal cells and cross-presented in vivo is unknown and controversial. To address this issue we have investigated the ability of fibroblasts stably expressing chicken ovalbumin constructs targeted to different subcellular compartments to cross-prime cytotoxic T lymphocytes. Although these transfectants generated similar amounts of the immunogenic ovalbumin peptide, their cross-priming activity differed markedly. Instead, the cells cross-priming ability correlated with their steady-state levels of ovalbumin protein and/or the physical form/location of the protein. Moreover, in subcellular fractionation experiments, the cross-priming activity colocalized with antigenic protein. In addition, depletion of intact protein antigen from these cell fractions eliminated their cross-priming activity. In contrast, the major heat shock protein candidates for cross-presentation were separable from the cell's main sources of cross-priming antigen. Therefore, cellular proteins, rather than peptides or heat shock protein/peptide complexes, are the major source of antigen that is transferred from antigen-bearing cells and cross-presented in vivo. (+info)
Antigen bias in T cell cross-priming.
(4/459)
Activated CD8+ T cells detect virally infected cells and tumor cells by recognition of major histocompatibility complex class I-bound peptides derived from degraded, endogenously produced proteins. In contrast, CD8+ T cell activation often occurs through interaction with specialized antigen-presenting cells displaying peptides acquired from an exogenous cellular source, a process termed cross-priming. Here, we observed a marked inefficiency in exogenous presentation of epitopes derived from signal sequences in mouse models. These data indicate that certain virus- and tumor-associated antigens may not be detected by CD8+ T cells because of impaired cross-priming. Such differences in the ability to cross-present antigens should form important considerations in vaccine design. (+info)
CD8+ T cell cross-priming via transfer of proteasome substrates.
(5/459)
"Cross-priming" describes the activation of naive CD8+ T cells by professional antigen-presenting cells that have acquired viral or tumor antigens from "donor" cells. Antigen transfer is believed to be mediated by donor cell-derived molecular chaperones bearing short peptide ligands generated by proteasome degradation of protein antigens. We show here that cross-priming is based on the transfer of proteasome substrates rather than peptides. These findings are potentially important for the rational design of vaccines that elicit CD8+ T cell responses. (+info)
Despite differences between dendritic cells and Langerhans cells in the mechanism of papillomavirus-like particle antigen uptake, both cells cross-prime T cells.
(6/459)
As human papillomavirus-like particles (HPV-VLP) represent a promising vaccine delivery vehicle, delineation of the interaction of VLP with professional APC should improve vaccine development. Differences in the capacity of VLP to signal dendritic cells (DC) and Langerhans cells (LC) have been demonstrated, and evidence has been presented for both clathrin-coated pits and proteoglycans (PG) in the uptake pathway of VLP into epithelial cells. Therefore, we compared HPV-VLP uptake mechanisms in human monocyte-derived DC and LC, and their ability to cross-present HPV VLP-associated antigen in the MHC class I pathway. DC and LC each took up virus-like particles (VLP). DC uptake of and signalling by VLP was inhibited by amiloride or cytochalasin D (CCD), but not by filipin treatment, and was blocked by several sulfated and non-sulfated polysaccharides and anti-CD16. In contrast, LC uptake was inhibited only by filipin, and VLP in LC were associated with caveolin, langerin, and CD1a. These data suggest fundamentally different routes of VLP uptake by DC and LC. Despite these differences, VLP taken up by DC and LC were each able to prime naive CD8(+) T cells and induce cytolytic effector T cells in vitro. (+info)
HIV-1 Nef equips dendritic cells to reduce survival and function of CD8+ T cells: a mechanism of immune evasion.
(7/459)
The accessory HIV-1 Nef protein is a crucial determinant for viral replication and pathogenesis. During HIV infection, loss of immune control in the setting of a strong and broad HIV-specific T-lymphocyte response, leads to a lethal outcome through AIDS. Moreover, dysfunction of dendritic cells (DCs) may contribute to the immune suppression associated with AIDS progression. We recently demonstrated that exogenous Nef selectively activates immature DCs manipulating their phenotypical, morphological, and functional developmental program. Here, we tracked whether Nef, targeting DCs, could be involved in the dysregulation of CD8+ T cell responses. We found that Nef inhibits the capacity of DCs to prime alloreactive CD8+ T cell responses down-regulating their proliferation and functional competence. This coincides with the induction of CD8+ T cell apoptosis. Nef oversees apoptotic killing of CD8+ T cells up-regulating TNF-alpha and FasL production by DCs and interfering with the death receptor pathway in CD8+ T cells and thus activating caspase 8. Our findings suggest that Nef may contribute to the immune evasion associated with HIV-1 infection, subverting DC biology. This may help explain the pleiotropic function that Nef plays during infection and makes this protein an attractive target for preventive and therapeutic intervention. (+info)
Mature human Langerhans cells derived from CD34+ hematopoietic progenitors stimulate greater cytolytic T lymphocyte activity in the absence of bioactive IL-12p70, by either single peptide presentation or cross-priming, than do dermal-interstitial or monocyte-derived dendritic cells.
(8/459)
The emerging heterogeneity of dendritic cells (DCs) mirrors their increasingly recognized division of labor at myriad control points in innate and acquired cellular immunity. We separately generated blood monocyte-derived DCs (moDCs), as well as Langerhans cells (LCs) and dermal-interstitial DCs (DDC-IDCs) from CD34(+) hematopoietic progenitor cells. Differential expression of CD11b, CD52, CD91, and the CD1 isoforms proved useful in distinguishing these three DC types. All mature DCs uniformly expressed comparable levels of HLA-DR, CD83, CD80, and CD86, and were potent stimulators of allogeneic T cells after exposure either to recombinant human CD40L trimer or a combination of inflammatory cytokines with PGE(2). moDCs, however, required 0.5-1 log greater numbers than LCs or DDC-IDCs to stimulate comparable T cell proliferation. Only moDCs secreted the bioactive heterodimer IL-12p70, and moDCs phagocytosed significantly more dying tumor cells than did either LCs or DDC-IDCs. LCs nevertheless proved superior to moDCs and DDC-IDCs in stimulating CTL against a recall viral Ag by presenting passively loaded peptide or against tumor Ag by cross-priming autologous CD8(+) T cells. LCs also secreted significantly more IL-15 than did either moDCs or DDC-IDCs, which is especially important to the generation of CTL. These findings merit further comparisons in clinical trials designed to determine the physiologic relevance of these distinctions in activity between LCs and other DCs. (+info)