Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
Experimental Transplantation and Immunotherapy Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
Mucosal Immunol. 2022 May;15(5):882-895. doi: 10.1038/s41385-022-00540-9. Epub 2022 Jul 1.
The chemokine receptor CCR9 equips T cells with the ability to respond to CCL25, a chemokine that is highly expressed in the thymus and the small intestine (SI). Notably, CCR9 is mostly expressed on CD8 but not on CD4 lineage T cells, thus imposing distinct tissue tropism on CD4 and CD8 T cells. The molecular basis and the consequences for such a dichotomy, however, have not been fully examined and explained. Here, we demonstrate that the forced expression of CCR9 interferes with the tissue trafficking and differentiation of CD4 T cells in SI intraepithelial tissues. While CCR9 overexpression did not alter CD4 T cell generation in the thymus, the forced expression of CCR9 was detrimental for the proper tissue distribution of CD4 T cells in the periphery, and strikingly also for their terminal differentiation in the gut epithelium. Specifically, the differentiation of SI epithelial CD4 T cells into immunoregulatory CD4CD8αα T cells was impaired by overexpression of CCR9 and conversely increased by the genetic deletion of CCR9. Collectively, our results reveal a previously unappreciated role for CCR9 in the tissue homeostasis and effector function of CD4 T cells in the gut.
趋化因子受体 CCR9 赋予 T 细胞对 CCL25 的反应能力，CCL25 是一种在胸腺和小肠 (SI) 中高度表达的趋化因子。值得注意的是，CCR9 主要表达在 CD8 但不在 CD4 谱系 T 细胞上，因此对 CD4 和 CD8 T 细胞施加了不同的组织趋向性。然而，这种二分法的分子基础和后果尚未得到充分检查和解释。在这里，我们证明 CCR9 的强制表达会干扰 CD4 T 细胞在 SI 上皮组织中的组织迁移和分化。虽然 CCR9 的过表达不会改变胸腺中 CD4 T 细胞的产生，但 CCR9 的强制表达不利于 CD4 T 细胞在外周组织中的适当分布，并且令人惊讶的是，也不利于它们在肠道上皮中的终末分化。具体而言，CCR9 的过表达会损害 SI 上皮 CD4 T 细胞分化为免疫调节性 CD4CD8αα T 细胞，而 CCR9 的基因缺失则会相反地增加这种分化。总之，我们的结果揭示了 CCR9 在肠道中 CD4 T 细胞的组织稳态和效应功能中的以前未被认识的作用。
