Tissue signals regulating commensal-specific CD8+ T cells

Abstract

A central challenge of host-microbiota mutualism is the need to balance antigen-specific immune recognition with durable tolerance. Commensal-specific T cells must be restrained under homeostatic conditions to prevent inappropriate tissue damage, while retaining the capacity to respond during infection or tissue injury. The intestinal epithelium harbors a large population of microbiota-dependent CD8αβ⁺ T cells whose antigen specificity and regulation are ill-defined. Furthermore, how epithelial signals are integrated to maintain antigen-experienced CD8⁺ T cells in a non-pathogenic state, particularly in the context of commensal colonization and continuous microbial antigen exposure, remains an open question. Despite their increasing implication in intestinal-immune pathologies, CD8+ IEL have remained understudied largely due to lack of tools to track this enigmatic population. My thesis research aimed to gain mechanistic understanding of how commensal-specific CD8+ T cell responses are induced, regulated, and maintained. To do this, I identified and cloned a CD8+ T cell receptor (TCR) specific to a gut microbe, enabling granular characterization of the mechanisms by which commensal-specific CD8+ IEL are restrained in the healthy gut, and how this restraint is lost during chronic intestinal inflammation. By identifying MHCIa-restricted TCRs and generating tetramers against the gut commensal Segmented Filamentous Bacteria, I was able to demonstrate that a single commensal species drives a clonally expanded, antigen-specific CD8αβ⁺ T cell population within the intraepithelial lymphocyte (IEL) compartment. Mechanistically, the intestinal epithelium coordinates coincident signals governing this population: peptide:MHC-dependent TCR engagement drives IEL accumulation, while αvβ6-mediated TGFβ activation restrains effector cell differentiation. Perturbation of epithelial cell-mediated TGFβ activation diverts commensal-specific CD8⁺ T cells toward inflammatory differentiation states transcriptionally convergent with those observed in ulcerative colitis. The intestinal epithelium thus functions as a dual-signal organizer of commensal-specific CD8⁺ T cell responses, coupling differentiation to restraint through spatially coincident molecular cues. Altogether, these findings reframe intestinal tolerance not as an absence of commensal-specific immunity, but as epithelially enforced restraint of commensal-specific CD8+ T cells and identify the αvβ6-TGFβ axis as a critical checkpoint whose disruption tips the balance from homeostasis to inflammation.