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Citrobacter rodentium Induces Tissue-Resident Memory CD4⁺ T Cells.

ABSTRACT: Tissue-resident memory T cells (T_RM cells) are a novel population of tissue-restricted antigen-specific T cells. T_RM cells are induced by pathogens and promote host defense against secondary infections. Although T_RM cells cannot be detected in circulation, they are the major memory CD4⁺ and CD8⁺ T-cell population in tissues in mice and humans. Murine models of CD8⁺ T_RM cells have shown that CD8⁺ T_RM cells maintain tissue residency via CD69 and though tumor growth factor β-dependent induction of CD103. In contrast to CD8⁺ T_RM cells, there are few models of CD4⁺ T_RM cells. Thus, much less is known about the factors regulating the induction, maintenance, and host defense functions of CD4⁺ T_RM cells. Citrobacter rodentium is known to induce IL-17⁺ and IL-22⁺ CD4⁺ T cells (T_h17 and T_h22 cells, respectively). Moreover, data from IL-22 reporter mice show that most IL-22⁺ cells in the colon 3 months after C. rodentium infection are CD4⁺ T cells. This collectively suggests that C. rodentium may induce CD4⁺ T_RM cells. Here, we demonstrate that C. rodentium induces a population of IL-17A⁺ CD4⁺ T cells that are tissue restricted and antigen specific, thus meeting the criteria of CD4⁺ T_RM cells. These cells expand and are a major source of IL-22 during secondary C. rodentium infection, even before the T-cell phase of the host response in primary infection. Finally, using FTY 720, which depletes circulating naive and effector T cells but not tissue-restricted T cells, we show that these CD4⁺ T_RM cells can promote host defense.

SUBMITTER: Bishu S

PROVIDER: S-EPMC6589064 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Citrobacter rodentium Induces Tissue-Resident Memory CD4+ T Cells.

Bishu S S Hou G G El Zaatari M M Bishu S R SR Popke D D Zhang M M Grasberger H H Zou W W Stidham R W RW Higgins P D R PDR Spence J R JR Kamada N N Kao J Y JY

Infection and immunity 20190620 7

Tissue-resident memory T cells (TRM cells) are a novel population of tissue-restricted antigen-specific T cells. TRM cells are induced by pathogens and promote host defense against secondary infections. Although TRM cells cannot be detected in circulation, they are the major memory CD4+ and CD8+ T-cell population in tissues in mice and humans. Murine models of CD8+ TRM cells have shown that CD8+ TRM</sub ...[more]

PMID: 31061145

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Project description:Pulmonary fibrosis is a devastating disease with no effective treatments to cure, stop or reverse the unremitting, fatal fibrosis. A critical barrier to treating this disease is the lack of understanding of the pathways leading to fibrosis as well as those regulating the resolution of fibrosis. Fibrosis is the pathologic side of normal tissue repair that results when the normal wound healing programs go awry. Successful resolution of tissue injury requires several highly coordinated pathways, and this research focuses on the interplay between these overlapping pathways: immune effectors, inflammatory mediators and fibroproliferation in the resolution of fibrosis. Previously we have successfully prevented, mitigated, and even reversed established fibrosis using vaccinia vaccination immunotherapy in two models of murine lung fibrosis. The mechanism by which vaccinia reverses fibrosis is by vaccine induced lung specific Th1 skewed tissue resident memory (TRMs) in the lung. In this study, we isolated a population of vaccine induced TRMs - CD49a+ CD4+ T cells - that are both necessary and sufficient to reverse established pulmonary fibrosis. Using adoptive cellular therapy, we demonstrate that intratracheal administration of CD49a+ CD4+ TRMs into established fibrosis, reverses the fibrosis histologically, by promoting a decrease in collagen, and functionally, by improving lung function, without the need for vaccination. Furthermore, co-culture of in vitro derived CD49+ CD4+ human TRMs with human fibroblasts from individuals with idiopathic pulmonary fibrosis (IPF) results in the down regulation of IPF fibroblast collagen production. Lastly, we demonstrate in human IPF lung histologic samples that CD49a+ CD4+ TRMs, which can down regulate human IPF fibroblast function, fail to increase in the IPF lungs, thus potentially failing to promote resolution. Thus, we define a novel unappreciated role for tissue resident memory T cells in regulating established lung fibrosis to promote resolution of fibrosis and re-establish lung homeostasis. We demonstrate that immunotherapy, in the form of adoptive transfer of CD49a+ CD4+ TRMs into the lungs of mice with established fibrosis, not only stops progression of the fibrosis but more importantly reverses the fibrosis. These studies provide the insight and preclinical rationale for a novel paradigm shifting approach of using cellular immunotherapy to treat lung fibrosis.

Dataset Information

Citrobacter rodentium Induces Tissue-Resident Memory CD4⁺ T Cells.

Publications

Citrobacter rodentium Induces Tissue-Resident Memory CD4<sup>+</sup> T Cells.

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