Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

Abstract

Tumor progression locus 2 (Tpl2) is a serine-threonine kinase that regulates Th1 differentiation, secretion of the inflammatory cytokine gamma interferon (IFN-␥), and host defense against the intracellular pathogens Toxoplasma gondii, Listeria monocytogenes, and Mycobacterium tuberculosis. However, relatively little is known about the contribution of Tpl2 to Th17 differentiation and immune cell function during infection with an extracellular pathogen. The goal of this study was to determine whether Tpl2 influences the immune response generated to the extracellular bacterium Citrobacter rodentium, which induces a mixed Th1 and Th17 response. During peak infection with C. rodentium, Tpl2 Ϫ/Ϫ mice experienced greater bacterial burdens with evidence of dissemination to the liver and spleen but ultimately cleared the bacteria within 3 weeks postinfection, similar to the findings for wild-type mice. Tpl2 Ϫ/Ϫ mice also recruited fewer neutrophils and monocytes to the colon during peak infection, which correlated with increased bacterial burdens. In mixed bone marrow chimeras, Tpl2 was shown to play a T cell-intrinsic role in promoting both IFN-␥ and interleukin-17A production during infection with C. rodentium. However, upon CD4 T cell transfer into Rag Ϫ/Ϫ mice, Tpl2 Ϫ/Ϫ CD4 T cells were as protective as wild-type CD4 T cells against the dissemination of bacteria and mortality. These data indicate that the enhanced bacterial burdens in Tpl2 Ϫ/Ϫ mice are not caused primarily by impairments in CD4 T cell function but result from defects in innate immune cell recruitment and function. KEYWORDS Citrobacter, T helper cells, gastrointestinal infection, intestinal immunity, neutrophilsC itrobacter rodentium is a nonmotile Gram-negative rod that is a natural mouse and gerbil pathogen (1, 2). Upon infection, C. rodentium colonizes the large intestine, primarily the cecum and distal portion of the colon (3), and forms a close association with the epithelium and lamina propria that results in attaching and effacing lesions in the large intestine (4, 5). However, C. rodentium can disseminate out of the intestines and be found in the nasopharynx, lung, heart, liver, and spleen (6). Early innate responses to C. rodentium are associated with recruitment and the antimicrobial functions of neutrophils, macrophages, NK cells, and innate lymphoid cells (7-12). Neutrophils secrete interleukin-17A (IL-17A) and IL-22, promote the production of antimicrobial defensins by epithelial cells, and protect against the development of diarrhea (11,13). The bacterial association with the lamina propria of the large intestine subsequently induces a mixed Th1 and Th17 response associated with IL-12, gamma interferon (IFN-␥), tumor necrosis factor (TNF), . Clearance of the bacteria occurs within 3 weeks in a wild-type host and is dependent upon both CD4 T cell and B cell functions (18, 19).Tumor progression locus 2 (Tpl2; also known as MAP3K8) is a serine-threonine Citation Acuff NV, Li X, Latha K, Nagy T, Watford WT. 2017. Tpl2 promotes innat...

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“…Typically, innate immune cells are recruited early during influenza infection to phagocytose or endocytose infected cells (35); therefore, it was unexpected to see such high numbers of them late in the infection in Tpl2 -/mice. Because Tpl2 deficiency has been demonstrated to impair monocyte, macrophage and neutrophil recruitment in response to inflammatory stimuli (21,(36)(37)(38)(39), we further assessed the kinetics for the paradoxically increased monocytes and neutrophils in the lung tissue of influenza-infected Tpl2 -/mice. Therefore, we characterized the cellular composition of lungs at an earlier time point (4 dpi) with uninfected mice as negative controls.…”