The relationship between MHC restricted and allospecific T cell recognition

Area of Science:

• Immunology
• T cell biology
• MHC restriction

Background:

• The high frequency of T cells recognizing allogeneic MHC molecules challenges the dogma of positive selection for self-MHC restriction.
• Investigating the origin of alloreactive T cells is crucial for understanding immune responses.

Purpose of the Study:

• To explore if alloreactive T cells originate from a non-self-MHC-restricted repertoire.
• To determine the contribution of in vivo-primed T cells to primary alloresponses.

Main Methods:

• Separated peripheral blood T cells into virgin and memory populations based on LFA-3 expression.
• Quantitated proliferative responses of T cells to MHC-incompatible stimulator cells.

Main Results:

• Approximately half of a primary alloresponse is mediated by previously primed, self-MHC-restricted T cells.
• Defined the MHC-restricted specificity of T cell clones recognizing allogeneic HLA-DR1.
• Structural analysis of DR beta 1 domains suggests allorecognition can mimic self-restricted recognition through shared histotopic residues.

Conclusions:

• Alloreactive T cells, like antigen-specific T cells, likely recognize MHC/peptide complexes with parental self-MHC restriction.
• Determinant selection of endogenous peptides bound by MHC molecules explains allorecognition within histotopically similar DR groups.
• Allorecognition in dissimilar MHC combinations may involve T cell receptors with intermediate affinity for self-MHC and higher affinity for allogeneic MHC.