OX40 and IL‐7 play synergistic roles in the homeostatic proliferation of effector memory CD4⁺ T cells

Abstract

T-cell homeostasis preserves the numbers, the diversity and functional competence of different T-cell subsets that are required for adaptive immunity. Naïve CD4 + T (T N ) cells are maintained in the periphery via the common γ-chain family cytokine IL-7 and weak antigenic signals. However, it is not clear how memory CD4 + T-cell subsets are maintained in the periphery and which factors are responsible for the maintenance. To examine the homeostatic mechanisms, CFSE-labeled CD4 + CD44 high CD62L low effector memory T (T EM ) cells were transferred into sublethally-irradiated syngeneic C57BL/6 mice, and the systemic cell proliferative responses, which can be divided distinctively into fast and slow proliferations, were assessed by CFSE dye dilution. We found that the fast homeostatic proliferation of T EM cells was strictly regulated by both antigen and OX40 costimulatory signals and that the slow proliferation was dependent on IL-7. The simultaneous blockade of both OX40 and IL-7 signaling completely inhibited the both fast and slow proliferation. The antigen-and OX40-dependent fast proliferation preferentially expanded IL-17-producing helper T cells (Th17 cells). Thus, OX40 and IL-7 play synergistic, but distinct roles in the homeostatic proliferation of CD4 + T EM cells.Keywords: Homeostatic proliferation r Memory CD4 + T cells r OX40 r Th17Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHomeostatic proliferation is a proliferative T-cell response induced by lymphopenia and helps control the size of the T-cell pool in the Correspondence: Prof. Naoto Ishii e-mail: ishiin@med.tohoku.ac.jp periphery [1,2]. This response not only contributes to the maintenance of T-cell homeostasis [1,2], but also to the pathogenesis of inflammatory diseases, including inflammatory bowel diseases (IBDs), graft versus host disease (GVHD), and type 1 diabetes * These authors contributed equally to this manuscript. Eur. J. Immunol. 2014. 44: 3015-3025 [ [3][4][5][6][7]. The homeostatic proliferation of naïve T (T N ) cells has been well studied by transferring T N cells into lymphopenic hosts, such as sublethally irradiated or Rag-deficient mice, and examining the division and differentiation of the donor cells in the spleen, lymph nodes, and gut tissues [8][9][10][11][12]. These studies demonstrated that the homeostatic proliferation of donor T N cells supplies a memoryphenotype T-cell pool [11,[13][14][15][16][17][18]. Notably, the T N cell populations undergoing homeostatic proliferation under lymphopenic conditions can be divided into two groups by their division rate: slow, in which the cells divide only one to three times per week, and fast, in which the cells divide more than seven times in a week [19]. The slow proliferation requires IL-7, occurs in secondary lymphoid organs, and produces a cell population that retains the naïve phenotype (CD44 low CD62L high ) and has limited differentiation potential [1,20,21]. In contrast, the fast proliferation...

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