A colitogenic memory CD4+ T cell population mediates gastrointestinal graft-versus-host disease
Vivian Zhou, … , Daniel J. Cua, William R. Drobyski
Vivian Zhou, … , Daniel J. Cua, William R. Drobyski
Published August 8, 2016
Citation Information: J Clin Invest. 2016;126(9):3541-3555. https://doi.org/10.1172/JCI80874.
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Research Article

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

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Figure 3

β2 Integrin–expressing CD4+ T cells have a biased central memory phenotype and increased expression of gut-homing molecules.

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β2 Integrin–expressing CD4+ T cells have a biased central memory phenoty...
(A) Representative dot plot depicting CD11b and CD11c expression on gated CD4+TCRβ+ T cells pooled from spleen and lymph nodes (peripheral and mesenteric) of a normal B6 mouse. (B) Representative dot plots depicting CD44 and CD62L expression on whole CD4+ T cells, CD4+ T cells that lacked expression of either β2 integrin, or CD4+ T cells that expressed at least 1 of the 2 β2 integrins. (C) Percentage of naive, central memory (CM), and effector memory (EM) CD4+ T cells in populations shown in B (n = 5 mice per group). Data are presented as the mean ± SEM. (D) Representative dot plots depicting IL-23R expression and background isotype staining on CD4+TCRβ+ T cells, CD4+ T cells that did not express either CD11b or CD11c, or CD4+ T cells that expressed at least 1 of these 2 β2 integrins. (E) Scatterplot of percentage of each cell population noted in D that expressed the IL-23R (n = 6 mice per group). (F) Scatterplot of the percentage of naive CD4+ T cells lacking expression of either β2 integrin or expressing CD11b alone, CD11c alone, or both CD11b and CD11c (n = 6/group) that expressed the IL-23R. (G) Representative histograms and scatterplots of mean fluorescence intensity of CD69, CCR9, and α4β7 expression on CD4+ T cells that lacked expression of either β2 integrin or CD4+ T cells that expressed at least 1 of these 2 integrins. Statistically significant differences were calculated using the log rank test and 2-tailed Mann-Whitney U test. **P < 0.01, ***P < 0.001.