Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
Immunity. 2024 Nov 12;57(11):2615-2633.e10. doi: 10.1016/j.immuni.2024.09.015. Epub 2024 Oct 14.
Tissue-resident memory T (T) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common T cell fate remains poorly understood. Here, we show that whereas skin T cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive T cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal T populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated T cell phenotype and function, a phenomenon mirrored in mice with increased microbial diversity. Together, our findings reveal RA as a fundamental component of the host-environment interaction that directs immunosurveillance in tissues.
组织驻留记忆 T（T）细胞是组织免疫的重要组成部分，它们存在于各种解剖部位，具有共同的转录框架。这些细胞如何整合不同的局部线索，采用共同的 T 细胞命运仍然知之甚少。在这里，我们表明，皮肤 T 细胞严格需要转化生长因子β（TGF-β）才能驻留于组织中，而其他部位的 T 细胞则利用代谢产物视黄酸（RA）来驱动替代分化途径，在肝脏中指导 TGF-β 独立的组织驻留程序，并与 TGF-β协同作用以驱动小肠中的 T 细胞。我们发现 RA 是维持肠道 T 细胞群体的长期需要的，部分原因是它阻止了它们的逆行迁移。此外，增强的 RA 信号转导调节了 T 细胞的表型和功能，这一现象在微生物多样性增加的小鼠中得到了反映。总之，我们的研究结果揭示了 RA 作为宿主-环境相互作用的一个基本组成部分，指导组织中的免疫监视。
