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Immunity. 2014 Aug 21;41(2):244-56. doi: 10.1016/j.immuni.2014.06.017.

Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation.

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Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
Fox Chase Cancer Center, Cancer Prevention & Control Program, Philadelphia, PA 19111, USA.
Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA. Electronic address:


The intestinal epithelium harbors large populations of activated and memory lymphocytes, yet these cells do not cause tissue damage in the steady state. We investigated how intestinal T cell effector differentiation is regulated upon migration to the intestinal epithelium. Using gene loss- and gain-of-function strategies, as well as reporter approaches, we showed that cooperation between the transcription factors T-bet and Runx3 resulted in suppression of conventional CD4(+) T helper functions and induction of an intraepithelial lymphocyte (IEL) program that included expression of IEL markers such as CD8αα homodimers. Interferon-γ sensing and T-bet expression by CD4(+) T cells were both required for this program, which was distinct from conventional T helper differentiation but shared by other IEL populations, including TCRαβ(+)CD8αα(+) IELs. We conclude that the gut environment provides cues for IEL maturation through the interplay between T-bet and Runx3, allowing tissue-specific adaptation of mature T lymphocytes.

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