T-cell alloreactivity is a well-established phenomenon, but its molecular basis has remained enigmatic. Although there are differences between T-cell recognition of conventional and allogeneic antigens, it has become increasingly clear that they share many similarities. Recent insights into the specificity of the T-cell receptor (TCR) for peptide and the seeming intrinsic affinity of the TCR for the surface of the MHC molecule have provided a better understanding of how the TCR and peptide-MHC complexes interact. Here, we highlight the similarities and differences between conventional and allogeneic recognition of TCR-peptide-MHC complexes, and discuss how our view of allorecognitionhas changed, as well as the implications for TCR specificity and T-cell development.
The molecular basis underlying the specificity of alloreactive T cells for peptide-major histocompatibility complex ligands has been elusive. Here we describe a screen of 60 I-E(k)-alloreactive T cells and 83 naturally processed peptides that identified 9 reactive T cells. Three of the T cells responded to multiple, distinct peptides that shared no sequence homology. These T cells recognized each peptide-major histocompatibility complex ligand specifically and used a distinct constellation of I-E(k) contact residues for each interaction. Our studies show that alloreactive T cells have a 'germline-encoded' capacity to recognize multiple, distinct ligands and thus show 'polyspecificity', not degeneracy. Our findings help to explain the high frequency of alloreactive T cells and provide insight into the nature of T cell specificity.
The TAP1 and LMP2 genes are central for class I MHC function and share a common promoter. Here, we analyze the molecular mechanism of IFN gamma up-regulation of TAP1 and LMP2. In vivo footprinting indicates IFN gamma up-regulates protein-DNA contacts at an IRF-E that is essential for the up-regulation of TAP1 and LMP2 by IFN gamma. Gel shift analysis indicates that this site binds IRF-1. The expression of TAP1 and LMP2 are both greatly reduced in IRF-1-deficient mice. Surface class I MHC as well as CD8+ T cells are reduced in IRF-1-/- mice. The role of IRF-1 in the regulation of TAP1 and LMP2 suggests a mechanism for the antiviral properties of IRF-1 and the unexpected deficiency of CD8+ T cells observed in IRF-1-/- mice.
Although CD4+ and CD8+ T cells differ in their positively selecting signal strength, endogenous positively selecting ligands have only been identified for MHC class I-restricted T cell receptors (TCRs). Here we screened for ligands that can positively select MHC class II-restricted TCRs, using thymocytes from four I-Ek restricted TCR transgenic mice and a large panel of self peptides. One peptide, gp250, induced positive selection of AND CD4+ T cells, had no homology with the AND TCR agonist ligand, and was recognized with a high degree of specificity. gp250 acted as a co-agonist to initiate activation and enhance survival of peripheral AND CD4+ T cells. Thus, positively selecting ligands play critical roles in thymocyte development and in the activation and maintenance of peripheral T cells.
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