MHC II Heterozygosity Limits T Cell Receptor Variability in CD4 T Cells

αβ T cell receptor (TCR) V(D)J genes code for billions of TCR combinations. However only some appear on peripheral T cells in any individual because, to mature, thymocytes must react with low affinity but not high affinity with thymus expressed MHC/peptides. MHC proteins are very polymorphic. Different alleles bind different peptides. Therefore any individual might express many different MHC alleles to ensure that some peptides from an invader are bound to MHC and activate T cells. However, most individuals express limited numbers of MHC alleles. To explore this we compared the TCR repertoires of naïve, CD4 T cells in mice expressing one or two MHC II alleles. Surprisingly, the TCRs in heterozygotes were less diverse that those in the sum of their MHC II homozygous relatives. Our results suggest that thymus negative selection cancels out the advantages of increased thymic positive selection in the MHC heterozygotes. The aim of this study was to find out how MHC heterogeneity affects the T cell receptor (TCR) repertoire of naive CD4 T cells in mice. This work aimed to provide a mechanistic link between genetic background and phenotypic TCR repertoire. The focus of this work is to address a basic unsolved immunological question. However, understanding how different MHC alleles dictate the specific selection of diverse TCR repertoires could have enormous practical use in guiding the development of personalized vaccines, in monitoring autoimmune development, and predicting the responses of patients to infectious disease or immunotherapy checkpoint blockade. Because it is, at the moment, impossible to identify all the TCRs expressed in an individual wild type mouse we bred animals on the C57BL/6 background that were heterozygous for TCRalpha expression and also expressed a transgenic TCRbeta chain and no other TCRbetas. Consequently, in these animals, the transgenic TCRbeta is the only one expressed and each T cell expresses a single, varying TCRalpha chain. Thus the TCR repertoire in the animal can be understood by sequencing the expressed TCRalpha genes. Deposited samples are RNA sequencing reads of these recombined TCRalpha genes. Animals of this genotype were bred to express on the C57BL/6 background, homozygously, H-2b, H-2f, H-2g7 or H-2s. MHC heterozygotes were produced by intercrossing these animals.