A colitogenic memory CD4(+) T cell population mediates gastrointestinal graft-versus-host disease

作者：Zhou Vivian; Agle Kimberle; Chen Xiao; Beres Amy; Komorowski Richard; Belle Ludovic; Taylor Carolyn; Zhu Fenlu; Haribhai Dipica; Williams Calvin B; Verbsky James; Blumenschein Wendy; Sadekova Svetlana; Bowman Eddie; Ballantyne Christie; Weaver Casey; Serody David A; Vincent Benjamin; Serody Jonathan; Cua Daniel J; Drobyski William R^*

来源：Journal of Clinical Investigation, 2016, 126(9): 3541-3555.

DOI：10.1172/JCI80874

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 beta(2) 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 alpha(4)beta(7), and CCR9. Using several complementary murine GVHD models, we determined that adoptive transfer and early accumulation of beta(2), 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.

• 出版日期2016-9