Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3695-700. doi: 10.1073/pnas.1017015108. Epub 2011 Feb 14.

Alloreactivity is limited by the endogenous peptide repertoire.

Author information

1
Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.

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.

PMID:
21321209
PMCID:
PMC3048116
DOI:
10.1073/pnas.1017015108
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center