Although the underlying mechanisms are not well understood, it is generally believed that antigen recognition by T cells in the absence of costimulation may alter the immune response, leading to anergy or tolerance. Further support for this concept comes from animal models of autoimmunity and transplantation, where treatments based on costimulation blockade, in particular CD40 ligand (CD40L)-specific antibodies, have been highly effective. We investigated the mechanisms of action of an antibody to CD40L and provide evidence that its effects are dependent on the constant (Fc) region. Prolongation of graft survival is dependent on both complement- and Fc receptor-mediated mechanisms in a major histocompatibility complex (MHC)-mismatched skin transplant model. These data suggest that antibodies to CD40L act through selective depletion of activated T cells, rather than exerting immune modulation by costimulation blockade as currently postulated. This finding opens new avenues for treatment of immune disorders based on selective targeting of activated T cells.
We have applied MHC class I tetramers representing the two H2b MHC class I-restricted epitopes of the mouse male-specific minor transplantation Ag, HY, to directly determine the extent of expansion and immunodominance within the CD8+ T cell compartment following exposure to male tissue. Immunization with male bone marrow (BM), spleen, dendritic cells (DCs) and by skin graft led to rapid expansion of both specificities occupying up to >20% of the CD8+ T cell pool. At a high dose, whole BM or spleen were found to be more effective at stimulating the response than BM-derived DCs. In vivo, immunodominance within the responding cell population was only observed following chronic Ag stimulation, whereas epitope immunodominance was established rapidly following in vitro restimulation. Peptide affinity for the restricting MHC molecule was greater for the immunodominant epitope, suggesting that this might be a factor in the emergence of immunodominance. Using tetramers, we were able to directly visualize the cross-primed CD8+ HY response, but we did not find it to be the principal route for MHC class I presentation. Immunization with female spleen or DCs coated with the full complement of defined HY peptides, including the Ab-restricted CD4+ Th cell determinant, failed to induce tetramer-reactive cells.
The physiologic significance of MHCpeptide complex presentation by endothelial cells (ECs) to trafficking T lymphocytes remains unresolved. On the basis of our observation that cognate recognition of ECs enhanced transendothelial migration of antigen-specific T lymphocytes in vitro, we have proposed that by displaying antigenic peptides from the underlying tissue, ECs promote the recruitment of antigen-specific T cells. In this study, we have tested this hypothesis by comparing the trafficking of HYspecific T lymphocytes into antigenic and nonantigenic tissue using in vivo models of T-cell recruitment. Up-regulated expression of H2 molecules presenting endogenous antigen in the peritoneal mesothelium and vessels led to the local recruitment of HY-specific T cells in male, but not female, mice. Intravital microscopy experiments analyzing EC-HYspecific T-cell interactions in the cremasteric vascular bed revealed that cognate recognition of the endothelium results in enhanced diapedesis of T cells into the tissue, while not affecting rolling and adhesion. Our results are consistent with the hypothesis that, under inflammatory conditions, antigen presentation by the endothelium contributes to the development and specificity of T-cell-mediated inflammation by favoring the selective migration of antigen-specific T cells. IntroductionLymphocyte recirculation and the localized recruitment and retention of antigen-specific T cells to sites of inflammation are key events in immune surveillance. While T-lymphocyte recirculation is constitutively regulated and occurs in the absence of inflammation, the development of an immune response depends on the recruitment and retention of specific T cells at antigenic sites, 1 thus minimizing collateral damage caused by non-antigenspecific inflammatory cells. T-cell migration into inflamed tissues involves sustained adhesive interactions with the microvascular endothelium that constitutively expresses major histocompatibility complex (MHC) molecules. Given that endothelial cells (ECs) may display tissue-specific as well as foreign peptides, 1,2 antigen presentation to migrating T cells is likely to occur during the adhesive interactions required for extravasation. The participation of T-cell receptor (TCR)-derived signals in actively promoting T-cell migration has been suggested by the observations that TCR triggering can induce integrin activation 3 and immobilize migrating T cells. 4 In addition, chemokine receptor expression by T cells is susceptible to TCR-mediated modulation. 5 A role for TCR signaling in the control of T-cell motility has also emerged from our recent studies on the functional consequences of antigen presentation by ECs to CD4 ϩ and CD8 ϩ T cells 6,7 in both human and murine systems. In addition, we showed that TCR triggering by the endothelium directly increased T-cell migration by inducing integrin activation. 6 A recent study has provided indirect evidence that insulin-specific clonal CD8 ϩ T cells require cognate recognition of pancreatic microvascular endo...
The evidence that proteasomes are involved in the processing of cross-presented proteins is indirect and based on the in vitro use of proteasome inhibitors. It remains, therefore, unclear whether cross-presentation of MHC class I peptide epitopes can occur entirely within phagolysosomes or whether it requires proteasome degradation. To address this question, we studied in vivo cross-presentation of an immunoproteasome-dependent epitope. First, we demonstrated that generation of the immunodominant HY Uty246–254 epitope is LMP7 dependent, resulting in the lack of rejection of male LMP7-deficient (LMP7−/−) skin grafts by female LMP7−/− mice. Second, we ruled out an altered Uty246–254-specific T cell repertoire in LMP7−/− female mice and demonstrated efficient Uty246–254 presentation by re-expressing LMP7 in male LMP7−/− cells. Finally, we observed that LMP7 expression significantly enhanced cross-priming of Uty246–254-specific T cells in vivo. The observations that male skin grafts are not rejected by LMP7−/− female mice and that presentation of a proteasome-dependent peptide is not efficiently rescued by alternative cross-presentation pathways provide strong evidence that proteasomes play an important role in cross-priming events.
How positive selection molds the T cell repertoire has been difficult to examine. In this study, we use TCR-β-transgenic mice in which MHC shapes TCR-α use. Differential AV segment use is directly related to the constraints placed on the composition of the CDR3 loops. Where these constraints are low, efficient selection of αβ pairs follows. This mode of selection preferentially uses favored AV-AJ rearrangements and promotes diversity. Increased constraint on the α CDR3 loops leads to inefficient selection associated with uncommon recombination events and limited diversity. Further, the two modes of selection favor alternate sets of AJ segments. We discuss the relevance of these findings to the imprint of self-MHC restriction and peripheral T cell activation.
Studies of human and murine T cells have shown that public TCR β-chain rearrangements can dominate the Ag-specific and naive repertoires of distinct individuals. We show that mouse T cells responding to the minor histocompatibility Ag HYDbSmcy share an invariant Vβ8.2-Jβ2.3 TCR gene rearrangement. The dominance of this rearrangement shows that it successfully negotiated thymic selection and was highly favored during clonal expansion in all animals examined. We hypothesized that such β-chains are advantaged during thymic and/or peripheral selection and, as a result, may be over-represented in the naive repertoire. A sequencing study was undertaken to examine the diversity of Vβ8.2-Jβ2.3 CDR3 loops from naive T cell repertoires of multiple mice. Public TCR β-chain sequences were identified across different repertoires and MHC haplotypes. To determine whether such public β-chains are advantaged during thymic selection, individual chains were followed through T cell development in a series of novel bone marrow competition chimeras. We demonstrate that β-chains were positively selected with similar efficiency regardless of CDR3 loop sequence. Therefore, the establishment and maintenance of public β-chains in the periphery is predominantly controlled by post-thymic events through modification of the primary, thymus-derived TCR repertoire.
Minor histocompatibility Ags derive from self-proteins and provoke allograft rejection and graft-vs-host disease in MHC-matched donor-recipient combinations. In this study, we define the HYDk epitope of the HY minor histocompatibility Ag as the 8mer peptide RRLRKTLL derived from the Smcy gene. Using HY tetramers, the response to this peptide was found to be immunodominant among the four characterized MHC class I-restricted HY epitopes (HYDkSmcy (defined here), HYKkSmcy, HYDbUty, and HYDbSmcy). Indirect presentation stimulated a robust primary HYDkSmcy response. Indirect presentation and priming of HY-specific CD8+ T cells is also operative in the presence of a full MHC mismatch. To determine whether the indirect route of Ag presentation is required for HY priming, female parent into F1 (H2bxk) female recipient bone marrow chimeras were immunized with male cells of the other parental haplotype, limiting presentation to the direct pathway. The dominant H2b HY response (HYDbUty) was dependent on indirect presentation. However, the dominant H2k HY response (HYDkSmcy) could be stimulated efficiently by the direct pathway. In contrast, secondary expansion of both HYDkSmcy and HYDbUty-specific CD8+ T cells was effective only when Ag was presented by the direct route. Transgenic overproduction of Smcy mRNA within the immunizing cells resulted in a corresponding increase in the HYDkSmcy, HYDbSmcy, and HYKkSmcy-specific CD8+ T cell responses when presented via the direct pathway but did not enhance indirect presentation demonstrating the independent regulation of MHC class I-peptide occupancy in the two Ag-processing pathways.
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