Self-tolerance alters T-cell receptor expression in an antigen-specific MHC restricted immune response

Abstract

The influence of major histocompatibility complex (MHC) gene products on the T-lymphocyte αβ receptor (TCR) repertoire is well documented^1–4, but how specificity is also generated for a diverse array of foreign peptide antigens is unknown. One proposed mechanism is that the TCR repertoire is selected by the recognition of processed self-antigens bound to MHC molecules^5,6. Here, we examine the influence of non-MHC-encoded self-antigens on the TCR repertoire expressed in an antigen-specific immune response. Most pigeon cytochrome c-specific, E^K_αE^K_β (E^k) Ia-restricted T cells from B10.A mice express a product of the V_α11 gene family in association with a V_β3 gene-encoded protein^7–10. We therefore examined V_α11 and V_β3 gene expression in cytochrome c-specific T-cell lines derived from various mouse strains with different non-MHC genetic backgrounds. T cells from several strains failed to express any V_β3 due to tolerance induced by Mls^c-encoded self-antigens^11,12. Variable levels of V_α11 messenger RNA (mRNA) were expressed by antigen-specific T cells from all the strains. In one strain V_β3 was expressed in the relative absence of V_α11. These results directly demonstrate that self-tolerance alters TCR gene usage in the immune response to a foreign antigen, and indicate that TCR V_α and V_β proteins may, in part, be independently selected.