BOTH MHC AND BACKGROUND GENE HETEROZYGOSITY ALTER T-CELL RECEPTOR REPERTOIRE SELECTION IN AN ANTIGEN-SPECIFIC RESPONSE

Many autoimmune diseases are associated with specific class II MHC all eles; however, this association is not complete. One explanation for t he variable expression of disease in susceptible individuals is that v ariability in the TCR repertoire may alter the potential to generate p athogenic autoreactive T cells. The current study was undertaken to ex amine the possibility that MHC and background heterozygosity, which is the norm in the outbred human population, alters the expressed TCR re pertoire and, if so, whether this has an impact on peptide recognition and antigenic specificity. We, therefore, systematically analysed the beef insulin-specific TCR repertoire in inbred BALB/c mice before and after introduction of MHC heterozygosity (BALB/c x BALB.K)F-1 mice, o r MHC and background gene heterozygosity (BALB/c x A/J)F-1 mice. We sh ow that T cells from all three repertoires are predominantly A(d)-rest ricted and recognize the same immunodominant peptide. Despite this, th e beef insulin-specific TCR repertoires in F-1 mice differ from those seen in BALB/c mice with the most dramatic changes seen in (BALB/c x A /J)F-1 mice. These changes are accompanied by subtle differences in th e antigenic specificity of the T cells. The results demonstrate that b oth MHC and background gene heterozygosity affect TCR repertoire selec tion, suggesting that the variable expression of autoimmune disease in individuals with a susceptible MHC allele may result, in part, from v ariability in the TCR repertoire introduced by this heterozygosity.