CD74 deficiency impairs Treg accumulation and function in the tumor. CD74 deficiency impairs Treg accumulation and function in the tumor

Regulatory T cells (Tregs) are known to actively adapt to the microenvironment in which they reside. However, how Tregs are reshaped in the tumor tissue remains under defined. We observed that in human tumors, Tregs selectively overexpress at the surface CD74, the MHC class II-associated invariant chain. Beyond its role in antigen presentation, CD74 has been described to impact gene transcription and cell migration, however, its role in Treg biology remains unknown. Here, we found that CD74KO Tregs exhibited major defects in the organization of their actin cytoskeleton and intracellular organelles and, consistently, they failed to accumulate in tumors and to suppress the anti-tumoral T-cell response. Strikingly, this phenotype did not result from a generic defect of CD74-deficient Tregs as their phenotype, proliferation, and suppressive function in vitro and in vivo during Graft-versus-Host disease were not affected. Our results reveal a new role for CD74 in Tregs and uncover CD74 potential as novel target to interfere with Treg anti-tumor activity. Overall design: Regulatory T cells isolated from healthy-donor blood are expanded for bulk-RNA sequencing analysis

调节性T细胞（Regulatory T cells, Tregs）可主动适配其所处的微环境，这一点已得到广泛认可。然而，肿瘤组织内的Tregs究竟如何被重塑，这一问题仍有待明确。本研究观察到，在人类肿瘤中，Tregs会在细胞表面选择性高表达CD74——即主要组织相容性复合体II类相关恒定链（MHC class II-associated invariant chain）。除参与抗原呈递外，CD74还被报道可影响基因转录与细胞迁移，但其在Treg生物学中的功能仍未可知。本研究发现，CD74敲除（CD74KO）的Tregs在肌动蛋白细胞骨架及胞内细胞器的组织层面存在显著缺陷；与之相一致的是，这些细胞无法在肿瘤组织中聚集，也无法抑制抗肿瘤T细胞应答。值得注意的是，该表型并非由CD74缺陷Tregs的一般性功能缺陷所致：在移植物抗宿主病（Graft-versus-Host disease, GvHD）进程中，这类细胞的表型、增殖能力以及体外与体内的抑制功能均未受到影响。本研究结果揭示了CD74在Tregs中的全新功能，并证实CD74有望成为干预Treg抗肿瘤活性的新型靶点。实验设计：从健康供者血液中分离调节性T细胞并进行扩增，以开展批量RNA测序分析。