Alloreactivity is limited by the endogenous peptide repertoire

Abstract

A significant portion of the naive T-cell repertoire is capable of responding to allogeneic MHC, violating the paradigm of self-MHC restriction. Recent studies have demonstrated convincing evidence for germ-line affinity of T-cell receptors (TCR) for MHC, providing explanation for recognition of MHC not encountered during thymic development. However, although germ-line affinity proposes all TCR have inherent affinity for MHC, most T cells are not alloreactive to a given MHC. We propose that specific recognition of endogenous presented peptides, rather than inability to interact with allogeneic MHC molecules, is the primary determinant of alloreactivity. Here, we demonstrate that alloreactive and nonalloreactive TCR differ specifically in the CDR3 sequences responsible primarily for the peptide specificity of T-cell recognition. Limitations on alloreactivity imposed by a requirement for recognition of presented peptides are directly demonstrated by expansion of the alloreactive T-cell repertoire through the addition of peptide mimotopes enabling response to two distinct allogeneic MHC by otherwise nonalloreactive T cells. Responses to peptide mimotopes were specific and depended on TCR interaction with MHC. These results demonstrate that recognition of presented endogenous peptides, and not the inability to interact with allogeneic MHC, is the primary limiter on alloreactivity. This observation reconciles the concept of an inherently MHC-reactive TCR repertoire with observed frequencies of T cells responding to allogeneic stimulation and underscores the fundamental nature of TCR recognition of ligands, where both MHC and presented peptides contribute critically to T-cell recognition.A lthough the diverse T-cell receptor (TCR) repertoire generated by germ-line V(D)J recombination is optimized during thymic selection for recognition of foreign antigens presented by self-MHC (1), it is hypothesized that response to MHC not encountered during thymic development is driven by inherent TCR affinity for MHC (2, 3). Recent studies have provided convincing evidence of germ-line affinity (4-8). However, it is not clear that response to allogeneic stimulation is determined primarily by the ability to make sufficient interactions between germ-line TCR elements and allogeneic MHC. Assessments of polyclonal alloreactive responses have demonstrated broad use of germ-line TCR segments (9, 10), suggesting that differential MHC affinity among germ-line elements does not account for differential alloreactivity among T cells. Conversely, analyses of non-germ-line-encoded CDR3 regions have demonstrated skewing in alloreactive responses. In a MHC-centric view of alloreactivity, CDR3 could determine alloreactivity through direct interaction with the MHC (11) or by imposing limitations on critical germ-line-encoded contacts (12).However, placing the entirety of determination for alloreactive potential on interaction with MHC does not address clear evidence for recognition of presented peptides in alloreactivity. Alterations to peptide pr...

Structural and energetic evidence for highly peptide-specific tumor antigen targeting via allo-MHC restriction

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Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness

“…Recognition of alloantigen by T cells is thought to be functionally similar to recognition of foreign antigen because CDR1 and CDR2 regions of the TCR interact with common determinants on polymorphic MHC molecules so that, as with foreign antigen, the principal interactions that promote cell activation are provided by foreign peptides (19,20). We therefore asked whether conventional antigen-specific responses are affected by GR deficiency.…”

Alloimmune T cells in transplantation

“…Thus, the TCR repertoire that is positively selected for low affinity to self-MHC/peptide and, by cross-reaction, receives higher affinity signals from foreign peptides presented by self-MHC, also has the potential to interact with high affinity to allogeneic MHC/peptide complexes. While some studies support the notion that the allo-MHC molecule alone is a major target of allorecognition (44,45), there is ample evidence that the combination of the allo-MHC and peptide underlies direct allorecognition (46)(47)(48)(49)(50)(51)(52), consistent with the notion of high-affinity cross-reactivity with allo-MHC/peptides of TCRs with low affinity for self-MHC/peptide. The ability of TCRs to recognize multiple different MHC/peptide combinations, or degeneracy, could explain a diverse, cross-reactive T cell alloresponse (53,54).…”