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 Transplantation

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 1

CD4+IL-23R+ T cells drive inflammation in the colon during GVHD.

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CD4+IL-23R+ T cells drive inflammation in the colon during GVHD. (A) BAL...
(A) BALB/c mice were transplanted with B6 BM alone (black circles, n = 12) or with B6 spleen cells. Animals transplanted with spleen cells were treated with an isotype control (black squares, n = 20) or anti–IL-23R antibody (white squares, n = 20). (B) BALB/c mice transplanted with BM from B6 (black circles, n = 12) or Il23r–/– (white circles, n = 12) donors or BM and spleen cells from B6 (black squares, n = 17) or Il23r–/– animals (white squares, n = 17). (C) BALB/c mice transplanted with B6 T cell depletion (TCD) BM cells (black circles, n = 9), B6 TCD BM plus 0.6 × 106 to 1.2 × 106 purified B6 T cells (black squares, n = 15), B6 TCD BM plus an equivalent number of Il23r–/– T cells (white squares, n = 15), or Il23r–/– TCD BM and B6 T cells (white triangles, n = 15). (D) BALB/c mice transplanted with B6 Rag-1 BM (black circles, n = 8) or with CD4+ T cells from B6 Il23r+/+ (black squares, n = 14) or Il23r–/– animals (white squares, n = 14). Survival data are from 3–4 experiments per panel. (E) BALB/c mice transplanted with B6 Rag-1 BM alone (circles, n = 5) or with purified CD4+ T cells from B6 (squares, n = 7) or Il23r–/– animals (triangles, n = 9). The absolute number of CD4+ T cells that secreted IFN-γ and/or IL-17 in the colon 3 weeks after transplantation. (F and G) BALB/c mice transplanted with B6 Rag-1 BM and a 1:1 mixture of CD4+ T cells from B6.PL Il23r+/+ and B6 Il23r–/– animals (WT/Il23r–/–) (triangles, n = 7–13), or B6 Rag-1 BM and a mixture of CD4+ T cells from B6.PL Il23r+/+ and B6 Il23r+/+ mice (WT/WT) (squares, n = 9–15). Ratio of CD4+ Thy1.1+/Thy1.2+ T cells and absolute number of CD4+Thy1.2+IFN-γ+ and Thy1.1+IFN-γ+ T cells is shown. Data in E–G are from 3 experiments. Statistically significant differences were calculated using the log rank test and 2-tailed Mann-Whitney U test. *P < 0.05, **P < 0.01, ***P < 0.001.