title: Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation.
abstract: 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.
authors.affiliation: Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Bernardo S
authors.initials: BS
authors.lastname: Reis
authors.affiliation: Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Hoytema van Konijnenburg
authors.affiliation: Fox Chase Cancer Center, Cancer Prevention & Control Program, Philadelphia, PA 19111, USA.
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Grivennikov
authors.affiliation: Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA. Electronic address: mucida@rockefeller.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mucida
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000276:immunology; D050677:Core Binding Factor Alpha 3 Subunit / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D018121:Receptors, Cytokine / Q000235:genetics; D017471:Receptors, Interferon / Q000235:genetics; D018123:Receptors, Interleukin; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology; D014212:Tretinoin; D015854:Up-Regulation; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor
chemical_list: D016827:CD8 Antigens; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D007378:Interleukins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018121:Receptors, Cytokine; D017471:Receptors, Interferon; D018123:Receptors, Interleukin; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D014212:Tretinoin; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor; C409469:CD8 antigen, alpha chain; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; C493730:Runx3 protein, mouse; C497211:Zbtb7b protein, mouse