Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally-occurring V𝛾4⁺V𝛿1⁺ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of V𝛾4⁺V𝛿1⁺ IELs was accompanied by the expansion of gluten-sensitive, interferon-𝛾-producing V𝛿1⁺ IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but failed to reconstitute the V𝛾4⁺V𝛿1⁺ ‘gut signature’ among TCR𝛾𝛿⁺ IELs. Collectively, these data demonstrate that chronic inflammation permanently reconfigures the tissue-resident TCR𝛾𝛿⁺ IEL compartment, thus the paradigm of tissue-resident lymphocyte stability needs revisiting.




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