Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Front Immunol. 2021 Jun 25;12:704578. doi: 10.3389/fimmu.2021.704578. eCollection 2021.
T cell anergy is a common mechanism of T cell tolerance. However, although anergic T cells are retained for longer time periods in their hosts, they remain functionally passive. Here, we describe the induction of anergic CD4 T cells by intravenous application of high doses of antigen and their subsequent conversion into suppressive Foxp3 IL-10 Tr1 cells but not Foxp3 Tregs. We describe the kinetics of up-regulation of several memory-, anergy- and suppression-related markers such as CD44, CD73, FR4, CD25, CD28, PD-1, Egr-2, Foxp3 and CTLA-4 in this process. The conversion into suppressive Tr1 cells correlates with the transient intracellular CTLA-4 expression and required the restimulation of anergic cells in a short-term time window. Restimulation after longer time periods, when CTLA-4 is down-regulated again retains the anergic state but does not lead to the induction of suppressor function. Our data require further functional investigations but at this stage may suggest a role for anergic T cells as a circulating pool of passive cells that may be re-activated into Tr1 cells upon short-term restimulation with high and systemic doses of antigen. It is tentative to speculate that such a scenario may represent cases of allergen responses in non-allergic individuals.
T 细胞无能是 T 细胞耐受的常见机制。然而，尽管无能的 T 细胞在其宿主中保留更长时间，但它们仍然保持功能上的被动。在这里，我们描述了通过静脉内给予高剂量抗原诱导无能的 CD4 T 细胞及其随后转化为抑制性 Foxp3+IL-10+Tr1 细胞而不是 Foxp3+Tregs。我们描述了在这个过程中几个记忆、无能和抑制相关标记物如 CD44、CD73、FR4、CD25、CD28、PD-1、Egr-2、Foxp3 和 CTLA-4 的上调的动力学。转化为抑制性 Tr1 细胞与细胞内 CTLA-4 表达的瞬时上调相关，并且需要在短时间窗口内对无能细胞进行再刺激。在更长时间后进行再刺激，当 CTLA-4 再次下调时，保持无能状态，但不会导致抑制功能的诱导。我们的数据需要进一步的功能研究，但在现阶段，可能表明无能 T 细胞作为循环池的被动细胞的作用，这些细胞可能在短时间内再次受到高剂量和全身性抗原的刺激后被激活为 Tr1 细胞。可以推测，这种情况可能代表非过敏个体中过敏原反应的情况。
