Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells

Abstract

Homeostatic proliferation of naive T cells in the spleen and cutaneous lymph nodes supplies memory–phenotype T cells. The “systemic” proliferative responses divide distinctly into fast or slow cell division rates. The fast proliferation is critical for generation of effector memory T cells. Because effector memory T cells are abundant in the lamina propria of the intestinal tissue, “gut-specific” homeostatic proliferation of naive T cells may be important for generation of intestinal effector memory T cells. However, such organ-specific homeostatic proliferation of naive T cells has not yet been addressed. In this study, we examined the gut-specific homeostatic proliferation by transferring CFSE-labeled naive CD4+ T cells into sublethally irradiated mice and separately evaluating donor cell division and differentiation in the intestine, mesenteric lymph nodes (MLNs), and other lymphoid organs. We found that the fast-proliferating cell population in the intestine and MLNs had a gut-tropic α4β7+ Th17 phenotype and that their production was dependent on the presence of commensal bacteria and OX40 costimulation. Mesenteric lymphadenectomy significantly reduced the Th17 cell population in the host intestine. Furthermore, FTY720 treatment induced the accumulation of α4β7+IL-17A+ fast-dividing cells in MLNs and eliminated donor cells in the intestine, suggesting that MLNs rather than intestinal tissues are essential for generating intestinal Th17 cells. These results reveal that MLNs play a central role in inducing gut-tropic Th17 cells and in maintaining CD4+ T cell homeostasis in the small intestine.

Mesenteric lymph nodes contribute to proinflammatory Th17‐cell generation during inflammation of the small intestine in mice

“…To clarify the specific role of MLNs in These results are consistent with the previous findings that MLNs are important for generating gut-homing Th17 but not Th1 cells [23]. In contrast, PP deficiency did not affect the absolute number of IFN-γ − IL-17A + or IFN-γ + IL-17A + cells, although their frequency among CD4 + cells was higher than in controls (Fig.…”

“…The removal of MLNs did not alter the composition of immune cell populations in the spleen and intestine (Supporting Information Fig. 2A and data not shown), nor dampen systemic immune responses, such as homeostatic proliferation [23,29]. In addition, deletion of PPs did not change splenic T-/B-cell populations (Supporting Information Fig.…”

“…In these organs, naïve T (T N ) cells, which primarily reside in the secondary lymphoid tissues [21], are primed and equipped with gut-homing receptors, such as α 4 β 7 integrin, to allow their differentiation into gut-tropic T EM cells upon Ag stimulation [22]. Besides, MLNs are also critically involved in the generation of gut-tropic Th17 cells from CD4 + T N cells [23,24], suggesting the possibility that MLNs or PPs might potentially contribute to not only non-inflammatory but also pathogenic T-cell generation in the small intestine. However, it is still unclear whether MLNs or PPs play a role in the pathogenesis of T-cell-mediated small intestinal inflammation, involving the generation of inflammatory Th17 cells, and how these two organs play their distinct roles in the inflammation.…”

TIR Domain-Containing Adapter-Inducing Beta Interferon (TRIF) Mediates Immunological Memory against Bacterial Pathogens

“…In this system, pathogen-experienced antigen-presenting cells (APCs) induce differentiation of cytotoxic and helper T (Th) cells that form pathogen-specific acquired immunity. Multiple types of Th cells are generated in local lymphoid tissues during infection, while Th17 cell generation is dominant in the intestine (1). The antibacterial properties of Th17 cells have been observed in lung infections with Gram-negative extracellular bacteria (2,3).…”

“…ϩ T cells and their functions via induction of the IFN signaling cascade in the MLN, where homeostatic proliferations of memory T cells are organized (1). Because the intestine serves as the Th17 cell factory in the body (35), targeting TRIF through intestinal mucosa may have additional potential for innovative vaccine strategies and to control many diseases that involve Th17 cell pathology.…”