Cochrane Russell W, Robino Rob A, Granger Bryan, Allen Eva, Vaena Silvia, Romeo Martin J, de Cubas Aguirre A, Berto Stefano, Ferreira Leonardo M R
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
Mol Ther Methods Clin Dev. 2024 Nov 18;32(4):101385. doi: 10.1016/j.omtm.2024.101385. eCollection 2024 Dec 12.
Regulatory T cells (Tregs) are promising cellular therapies to induce immune tolerance in organ transplantation and autoimmune disease. The success of chimeric antigen receptor (CAR) T cell therapy for cancer has sparked interest in using CARs to generate antigen-specific Tregs. Here, we compared CAR with endogenous T cell receptor (TCR)/CD28 activation in human Tregs. Strikingly, CAR Tregs displayed increased cytotoxicity and diminished suppression of antigen-presenting cells and effector T (Teff) cells compared with TCR/CD28-activated Tregs. RNA sequencing revealed that CAR Tregs activate Teff cell gene programs. Indeed, CAR Tregs secreted high levels of inflammatory cytokines, with a subset of FOXP3 CAR Tregs uniquely acquiring CD40L surface expression and producing IFN-γ. Interestingly, decreasing CAR antigen affinity reduced Teff cell gene expression and inflammatory cytokine production by CAR Tregs. Our findings showcase the impact of engineered receptor activation on Treg biology and support tailoring CAR constructs to Tregs for maximal therapeutic efficacy.
调节性T细胞（Tregs）是在器官移植和自身免疫性疾病中诱导免疫耐受的有前景的细胞疗法。嵌合抗原受体（CAR）T细胞疗法在癌症治疗中的成功引发了人们对使用CAR来产生抗原特异性Tregs的兴趣。在此，我们比较了CAR与内源性T细胞受体（TCR）/CD28激活在人Tregs中的作用。令人惊讶的是，与TCR/CD28激活的Tregs相比，CAR Tregs表现出细胞毒性增加，对抗原呈递细胞和效应T（Teff）细胞的抑制作用减弱。RNA测序显示，CAR Tregs激活了Teff细胞基因程序。事实上，CAR Tregs分泌高水平的炎性细胞因子，一部分FOXP3 CAR Tregs独特地获得CD40L表面表达并产生IFN-γ。有趣的是，降低CAR抗原亲和力可减少CAR Tregs的Teff细胞基因表达和炎性细胞因子产生。我们的研究结果展示了工程受体激活对Treg生物学的影响，并支持为实现最大治疗效果而针对Tregs定制CAR构建体。
