A colitogenic memory CD4+ T cell population mediates gastrointestinal graft-versus-host disease
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
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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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 5

CD4+CD11c+ T cells drive inflammation in the colon during GVHD.

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CD4+CD11c+ T cells drive inflammation in the colon during GVHD. (A) Base...
(A) Baseline IL-23R expression on gated CD4+ T cells from the spleen and lymph nodes of normal wild-type, Cd11b−/−, or Cd11c−/− mice. (B and C) BALB/c mice transplanted with B6 Rag-1 BM alone (black circles, n = 9) or with 0.8 × 106 CD4+ T cells from wild-type (black squares, n = 15), Cd11b–/– (white squares, n = 15), or Cd11c–/– (white triangles, n = 10) animals. Overall survival and serial weight curves are shown. (D) Representative dot plot depicting CD44 and CD62L expression on gated CD4+CD11c+ and CD4+CD11b+ T cells from Cd11b–/– and Cd11c–/– animals, respectively. (E) Percentage of CD4+CD11b+ (black bars) and CD4+CD11c+ (white bars) T cells with naive, central memory (CM), or effector memory (EM) phenotypes (n = 4). Data are presented as mean ± SEM. (F) Representative histograms of CCR9 and α4β7 expression on CD4+ T cells from Cd11b–/– (blue) or Cd11c–/– (pink) mice based on presence (open histograms) or absence (filled histograms) of CD11b or CD11c. Scatterplots of mean fluorescence intensity of CCR9 and α4β7 expression on CD4+ T cells from replicate animals are also depicted. (G) Hierarchical clustering of 684 genes that were significantly regulated in flow-sorted CD4+CD11c+CD44hiCD62L+ versus CD4+CD11c–CD44hiCD62L+ T cells from wild-type mice. S1–S3 refer to independent replicate samples with each replicate derived from pooled spleen and lymph node cells from 3–4 mice. Z score denotes SD. (H) Waterfall plot showing log2 fold difference in gene expression of differentially regulated genes. Red bars denote genes that had increased expression in CD4+CD11c+CD44hiCD62L+ T cells, while blue bars depict genes with decreased expression relative to CD4+CD11c−CD44hiCD62L+ T cells. Statistically significant differences were calculated using the log rank test and 2-tailed Mann-Whitney U test. *P < 0.05, ***P < 0.001.