Coincident epithelial signals restrain commensal-specific CD8αβ+ T cells in the intestine

Olsen, T. M.; Dufort, M. J.; Verma, S.; Makani, V. K. K.; Cameron, B.; Gralen, A. R.; Johnson, A. J.; Joglekar, A. V.; Byrd, A. L.; Lacy-Hulbert, A.; Harrison, O. J.

doi:10.64898/2026.04.29.720676

bioRxiv · 10.64898/2026.04.29.720676

Coincident epithelial signals restrain commensal-specific CD8αβ+ T cells in the intestine

Olsen, T. M.·Dufort, M. J.·Verma, S.·Makani, V. K. K.·Cameron, B.·Gralen, A. R.·Johnson, A. J.·Joglekar, A. V.·Byrd, A. L.·Lacy-Hulbert, A.·Harrison, O. J.

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Abstract

The intestinal epithelium harbors a large population of microbiota-dependent CD8{beta}+ T cells whose antigen specificity and regulation are ill-defined. By identifying MHCIa-restricted TCRs and generating tetramers against the gut commensal Segmented Filamentous Bacteria, we demonstrate that a single commensal species drives a clonally expanded, antigen-specific CD8{beta}+ T cell within the intraepithelial lymphocyte compartment. Mechanistically, the intestinal epithelium coordinates coincident signals governing this population: peptide:MHC-dependent TCR engagement drives pIEL accumulation, while v{beta}6-mediated TGF{beta} activation restraints effector cell differentiation. Perturbation of epithelial cell-mediated TGF{beta} 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.

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Olsen, T. M., Dufort, M. J., Verma, S., Makani, V. K. K., Cameron, B., Gralen, A. R., Johnson, A. J., Joglekar, A. V., Byrd, A. L., Lacy-Hulbert, A., Harrison, O. J.. 2026-05-04. Coincident epithelial signals restrain commensal-specific CD8αβ+ T cells in the intestine. https://doi.org/10.64898/2026.04.29.720676

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