Intestinal intraepithelial lymphocyte repertoires are imprinted clonal structures selected for MHC reactivity

Abstract

The intestinal mucosa is an important barrier for maintaining homeostasis and immune tolerance. Residing in the gut mucosa are the intestinal intraepithelial lymphocytes (IELs), an unconventional T cell type expressing αβ T cell receptors (TCRs) thought to contribute in immune surveillance and mediate repair of damaged epithelium. IELs are in close contact with a stream of microbial, food, and self-antigens, and while TCR-antigen interaction is presumed the major mechanism governing their functions, little is known about the native TCRαβ-IEL repertoire or its specificity. Previously, we developed a nearest-neighbor distance measurement (TCRdist) for quantifying convergence within TCR repertoires based on enriched features within their determinants of specificity. Here, we extended TCRdist to develop two novel tools for repertoire analysis: RepDist, for measuring similarity between repertoires, and TStar, for identifying repertoire-enriched features. We applied these to conduct a survey of the 'normal' TCR repertoires for three major subsets (CD8αα+, CD8, CD4) of IELs, under varying conditions of microbiome depletion, food antigen deprivation, MHC-deficiency, and combinations thereof. Surprisingly, the only perturbations that disrupted the IEL repertoire were deficiencies in Class I molecules or β2m. Food antigen and microbiome depletion had virtually no effect on the clonotypic composition of all three IEL subsets. MHC-substitution also had little effect, indicating that while Class I is required for CD8αα and CD8 IEL selection, it is haplotype-independent. Taken together, these data demonstrate the native IEL TCR repertoires are selected for self-reactivity, rather than specificity towards exogenous antigens.

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