Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Surgery, Guthrie Robert Packer Hospital, Sayre, Pennsylvania, USA.
JCI Insight. 2021 Nov 8;6(21):e149656. doi: 10.1172/jci.insight.149656.
Foxp3+ Tregs are potent immunosuppressive CD4+ T cells that are critical to maintain immune quiescence and prevent autoimmunity. Both the generation and maintenance of Foxp3+ Tregs depend on the cytokine IL-2. Hence, the expression of the IL-2 receptor α-chain (CD25) is not only considered a specific marker, but also a nonredundant requirement for Tregs. Here, we report that Foxp3+ Tregs in the small intestine (SI) epithelium, a critical barrier tissue, are exempt from such an IL-2 requirement, since they had dramatically downregulated CD25 expression, showed minimal STAT5 phosphorylation ex vivo, and were unable to respond to IL-2 in vitro. Nonetheless, SI epithelial Tregs survived and were present at the same frequency as in other lymphoid organs, and they retained potent suppressor function that was associated with high levels of CTLA-4 expression and the production of copious amounts of IL-10. Moreover, adoptive transfer experiments of Foxp3+ Tregs revealed that such IL-2-independent survival and effector functions were imposed by the SI epithelial tissue, suggesting that tissue adaptation is a mechanism that tailors the effector function and survival requirements of Foxp3+ Tregs specific to the tissue environment.
Foxp3+ Tregs 是具有强大免疫抑制功能的 CD4+ T 细胞，对于维持免疫静止和防止自身免疫至关重要。Foxp3+ Tregs 的产生和维持都依赖于细胞因子 IL-2。因此，IL-2 受体 α 链（CD25）的表达不仅被认为是一个特异性标记，而且是 Tregs 的一个非冗余要求。在这里，我们报告说，在小肠（SI）上皮这一关键的屏障组织中，Foxp3+ Tregs 豁免了这种 IL-2 需求，因为它们显著地下调了 CD25 的表达，体外表现出最小的 STAT5 磷酸化，并且无法对 IL-2 作出反应。尽管如此，SI 上皮 Tregs 仍然存活，并以与其他淋巴器官相同的频率存在，并且它们保留了强大的抑制功能，这与高水平的 CTLA-4 表达和大量 IL-10 的产生有关。此外，Foxp3+ Tregs 的过继转移实验表明，这种 IL-2 非依赖性的存活和效应功能是由 SI 上皮组织施加的，这表明组织适应是一种机制，专门针对组织环境调整 Foxp3+ Tregs 的效应功能和存活要求。
