Winstead Colleen J, Fraser Joanne M, Khoruts Alexander
Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
J Immunol. 2008 Jun 1;180(11):7305-17. doi: 10.4049/jimmunol.180.11.7305.
Regulatory CD4(+)CD25(+)Foxp3(+) T cells play a critical role in controlling autoimmunity and T cell homeostasis. However, their role in regulation of lymphopenia-induced proliferation (LIP), a potential mechanism for generation of autoaggressive T cells, has been poorly defined. Currently, two forms of LIP are recognized: spontaneous and homeostatic. Spontaneous LIP is characterized by fast, burst-like cell-cycle activity, and may allow effector T cell differentiation. Homeostatic LIP is characterized by slow and steady cell cycle activity and is not associated with the acquisition of an effector phenotype. In this study, we demonstrate that CD4(+)CD25(+)Foxp3(+) T cells suppress the spontaneous, but not homeostatic, LIP of naive CD8 and CD4 T cells. However, selective inhibition of spontaneous LIP does not fully explain the tolerogenic role of Tregs in lymphopenia-associated autoimmunity. We show here that suppression of LIP in the lymphoid tissues is independent of Treg-derived IL-10. However, IL-10-deficient Tregs are partially defective in their ability to prevent colitis caused by adoptive transfer of CD4 T cells into RAG(-/-) mice. We propose that Tregs may inhibit emergence of effector T cells during the inductive phase of the immune response in the secondary lymphoid tissues by IL-10-independent mechanisms. In contrast, Treg-mediated inhibition of established effector T cells does require IL-10. Both Treg functions appear to be important in control of lymphopenia-associated autoimmunity.
调节性CD4(+)CD25(+)Foxp3(+) T细胞在控制自身免疫和T细胞稳态中起关键作用。然而，它们在淋巴细胞减少诱导的增殖（LIP）调节中的作用，这是产生自身攻击性T细胞的一种潜在机制，目前还不清楚。目前，LIP有两种形式：自发性和稳态性。自发性LIP的特征是快速、爆发样的细胞周期活动，可能允许效应T细胞分化。稳态性LIP的特征是缓慢而稳定的细胞周期活动，与效应表型的获得无关。在本研究中，我们证明CD4(+)CD25(+)Foxp3(+) T细胞抑制幼稚CD8和CD4 T细胞的自发性而非稳态性LIP。然而，对自发性LIP的选择性抑制并不能完全解释调节性T细胞在淋巴细胞减少相关自身免疫中的致耐受性作用。我们在此表明，淋巴组织中LIP的抑制与调节性T细胞衍生的IL-10无关。然而，IL-10缺陷的调节性T细胞在预防CD4 T细胞过继转移到RAG(-/-)小鼠中所引起的结肠炎的能力上存在部分缺陷。我们提出，调节性T细胞可能通过不依赖IL-10的机制在次级淋巴组织免疫反应的诱导阶段抑制效应T细胞的出现。相比之下，调节性T细胞介导的对已建立的效应T细胞的抑制确实需要IL-10。这两种调节性T细胞功能在控制淋巴细胞减少相关自身免疫中似乎都很重要。
