Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Brazil.
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Front Immunol. 2024 Oct 21;15:1475146. doi: 10.3389/fimmu.2024.1475146. eCollection 2024.
Cytotoxic activity is a hallmark of the immunopathogenesis in human cutaneous leishmaniasis (CL). In this study, we identified accumulation of CD4 granzyme B producing T cells with increased cytotoxic capacity in CL lesions. These cells showed enhanced expression of activating NK receptors (NKG2D and NKG2C), diminished expression of inhibitory NKG2A, along with the upregulation of the senescence marker CD57. Notably, CD4 T cells freshly isolated from CL lesions demonstrated remarkable capacity to mediate NL-like bystander cytolysis. Phenotypic analyses revealed that lesional CD4 T cells are mainly composed of late-differentiated effector (CD27-CD45RA-) and terminally differentiated (senescent) TEMRA (CD27-CD45RA+) subsets. Interestingly, the TEMRA CD4 T cells exhibited higher expression of granzyme B and CD107a. Collectively, our results provide the first evidence that senescent cytotoxic CD4 T cells may support the skin pathology of human cutaneous leishmaniasis and, together with our previous findings, support the notion that multiple subsets of cytotoxic senescent cells may be involved in inducing the skin lesions in these patients.
细胞毒性活性是人类皮肤利什曼病（CL）免疫发病机制的标志。在这项研究中，我们发现 CL 病变中积累了具有增强细胞毒性的 CD4 颗粒酶 B 产生 T 细胞。这些细胞表现出活化 NK 受体（NKG2D 和 NKG2C）的表达增强，抑制性 NKG2A 的表达减少，以及衰老标志物 CD57 的上调。值得注意的是，从 CL 病变中新鲜分离的 CD4 T 细胞表现出介导 NL 样旁观者细胞溶解的显著能力。表型分析显示，病变 CD4 T 细胞主要由晚期分化效应（CD27-CD45RA-）和终末分化（衰老）TEMRA（CD27-CD45RA+）亚群组成。有趣的是，TEMRA CD4 T 细胞表现出更高水平的颗粒酶 B 和 CD107a 的表达。总的来说，我们的研究结果首次提供了证据表明衰老的细胞毒性 CD4 T 细胞可能支持人类皮肤利什曼病的皮肤病理学，并且与我们之前的发现一起，支持了多个细胞毒性衰老细胞亚群可能参与诱导这些患者皮肤损伤的观点。
