title: A colitogenic memory CD4+ T cell population mediates gastrointestinal graft-versus-host disease.
abstract: Damage to the gastrointestinal tract is a major cause of morbidity and mortality in graft-versus-host disease (GVHD) and is attributable to T cell-mediated inflammation. In this work, we identified a unique CD4+ T cell population that constitutively expresses the β2 integrin CD11c and displays a biased central memory phenotype and memory T cell transcriptional profile, innate-like properties, and increased expression of the gut-homing molecules α4β7 and CCR9. Using several complementary murine GVHD models, we determined that adoptive transfer and early accumulation of β2 integrin-expressing CD4+ T cells in the gastrointestinal tract initiated Th1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality. The pathogenic effect of this CD4+ T cell population critically depended on coexpression of the IL-23 receptor, which was required for maximal inflammatory effects. Non-Foxp3-expressing CD4+ T cells produced IL-10, which regulated colonic inflammation and attenuated lethality in the absence of functional CD4+Foxp3+ T cells. Thus, the coordinate expression of CD11c and the IL-23 receptor defines an IL-10-regulated, colitogenic memory CD4+ T cell subset that is poised to initiate inflammation when there is loss of tolerance and breakdown of mucosal barriers.
authors: Vivian
authors: V
authors: Zhou
authors: Kimberle
authors: K
authors: Agle
authors: Xiao
authors: X
authors: Chen
authors: Amy
authors: A
authors: Beres
authors: Richard
authors: R
authors: Komorowski
authors: Ludovic
authors: L
authors: Belle
authors: Carolyn
authors: C
authors: Taylor
authors: Fenlu
authors: F
authors: Zhu
authors: Dipica
authors: D
authors: Haribhai
authors: Calvin B
authors: CB
authors: Williams
authors: James
authors: J
authors: Verbsky
authors: Wendy
authors: W
authors: Blumenschein
authors: Svetlana
authors: S
authors: Sadekova
authors: Eddie
authors: E
authors: Bowman
authors: Christie
authors: C
authors: Ballantyne
authors: Casey
authors: C
authors: Weaver
authors: David A
authors: DA
authors: Serody
authors: Benjamin
authors: B
authors: Vincent
authors: Jonathan
authors: J
authors: Serody
authors: Daniel J
authors: DJ
authors: Cua
authors: William R
authors: WR
authors: Drobyski
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D049109:Cell Proliferation; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology*; D006801:Humans; D007118:Immunoassay; D007156:Immunologic Memory; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D018123:Receptors, Interleukin / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D039521:CD11c Antigen; D018821:CD18 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D018123:Receptors, Interleukin; C528688:interleukin-23 receptor, mouse; D016753:Interleukin-10