DataSheet1_Excess generation and activation of naturally arising memory-phenotype CD4+ T lymphocytes are inhibited by regulatory T cells in steady state.pdf

Conventional CD4+ T lymphocytes consist of naïve, foreign antigen-specific memory, and self-antigen-driven memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells tonically proliferate in response to self-antigens and differentiate into the T-bet+ subset in steady state. How excess proliferation and differentiation of MP cells are inhibited remains unclear. Given immunosuppressive function of regulatory T cells (Tregs), it is possible that they are also involved in inhibition of spontaneous MP cell activation. Here we show using Foxp3-diphtheria toxin receptor-transgenic mice that both MP and naïve CD4+ T cells spontaneously proliferate and differentiate into Th1 cells upon acute Treg depletion. At an early time point post Treg depletion, MP as compared to naïve CD4+ T cells are preferentially activated while at a later stage, the response is dominated by activated cells originated from the naïve pool. Moreover, we argue that MP cell proliferation is driven by TCR and CD28 signaling whereas Th1 differentiation mediated by IL-2. Furthermore, our data indicate that such activation of MP and naïve CD4+ T lymphocytes contribute to development of multi-organ inflammation at early and later time points, respectively, after Treg ablation. Together our findings reveal that Tregs tonically inhibit early, spontaneous proliferation and Th1 differentiation of MP CD4+ T lymphocytes as well as late activation of naïve cells, thereby contributing to maintenance of T cell homeostasis.

传统CD4+ T淋巴细胞在稳态下由原初型、外源抗原特异性记忆细胞以及由自身抗原驱动的记忆表型（MP）细胞组成。近期研究显示，MP细胞在接触到自身抗原时呈现持续的增殖状态，并在稳态下分化为T-bet+亚群。然而，MP细胞过度增殖和分化的抑制机制尚不明确。鉴于调节性T细胞（Tregs）具有免疫抑制功能，它们可能在抑制MP细胞的自发性激活过程中亦扮演重要角色。本研究利用Foxp3-白喉毒素受体转基因小鼠，发现MP和原初CD4+ T细胞在急性Treg耗竭后可自发增殖并分化为Th1细胞。在Treg耗竭后的早期时间点，与原初CD4+ T细胞相比，MP细胞优先被激活；而在晚期阶段，反应主要由源自原初池的激活细胞主导。此外，我们认为MP细胞的增殖受TCR和CD28信号通路驱动，而Th1分化则由IL-2介导。进一步的数据表明，MP和原初CD4+ T淋巴细胞的这种激活分别在不同时间点促进了多器官炎症的发展。综合我们的研究结果表明，Tregs通过抑制MP CD4+ T淋巴细胞的早期自发性增殖和Th1分化，以及晚期的原初细胞激活，从而有助于维持T细胞的稳态。