Abstract
Intestinal intraepithelial lymphocytes (IELs) form an unconventional T cell population demarcated by agonistic selection in the thymus before populating the gut mucosa, where it is thought they contribute in surveillance, homeostasis, and epithelial repair. Although IELs have been implicated in diseases affecting the gut, much remains to be understood about their selection and specificity. Integrating T cell receptor (TCR) repertoire sequencing and transcriptional profiling, we identify characteristic TCR features of induced CD4-, CD8-, and natural-IEL subsets and furthermore describe for the first time the human natural IEL subset. Depletion of microbial and dietary antigens alone or in combination did little to affect the underlying structure of each subset’s TCR repertoire. In contrast, disruption of β2m-dependent pathways abrogated public features that distinguished the natural IEL repertoires. These findings support a model for imprinting of TCRαβ-IEL repertoires based on competition among similar clonotypes selected for specificity to ubiquitous, conserved, β2m-dependent self-antigens.
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