Schroth Samantha L, Zhang Lei, Jones Rebecca Tl, Glinton Kristofor, Mani Nikita L, Inui Hiroyasu, Davidson Jesse T, Weinberg Samuel E, Chandel Navdeep S, Alegre Maria-Luisa, Thorp Edward B
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
J Clin Invest. 2025 Jul 10;135(18). doi: 10.1172/JCI178960. eCollection 2025 Sep 16.
The role of conventional type 1 DCs (cDC1s) in tolerance induction to solid organ allografts is unknown and important for strategies that seek to prolong allograft viability. Using a murine model deficient in cDC1s, we report cDC1s are required for donor antigen and costimulation blockade (DST + CoB) tolerance induction and survival of cardiac allografts. cDC1 deficiency led to decreases in CD4+CD25+FoxP3+ T cells within allograft and spleen tissue of transplant recipients, and this was found to be antigen specific. Donor antigen stimulation induced TGF-β1 expression in both in vivo cDC1s and in vitro Flt3L-derived cDC1s. Genetic deletion of TGF-β1 in cDC1s prevented induction of antigen-specific CD4+CD25+FoxP3+ T cells and was associated with cardiac allograft rejection. In parallel, single-cell RNA sequencing and metabolic analysis revealed upregulation of cDC1 mitochondrial metabolic signatures after in vivo exposure to DST + CoB. Genetic inactivation of cDC1 mitochondrial metabolism reduced expression of cDC1 TGF-β1, decreased antigen-specific Treg populations, and impaired allograft tolerance. Taken together, our findings implicate cDC1s in strategies to preserve solid organ allografts and also implicate mitochondrial metabolism of cDC1s as a molecular mechanism to enhance the generation of antigen-specific CD4+CD25+FoxP3+ T cells through TGF-β1.
传统1型树突状细胞（cDC1s）在实体器官同种异体移植耐受诱导中的作用尚不清楚，对于旨在延长同种异体移植存活期的策略而言至关重要。利用缺乏cDC1s的小鼠模型，我们报告称cDC1s是供体抗原和共刺激阻断（DST + CoB）耐受诱导及心脏同种异体移植存活所必需的。cDC1缺陷导致移植受者同种异体移植组织和脾脏组织中CD4 + CD25 + FoxP3 + T细胞减少，且发现这具有抗原特异性。供体抗原刺激在体内cDC1s和体外Flt3L衍生的cDC1s中均诱导TGF-β1表达。cDC1s中TGF-β1的基因缺失阻止了抗原特异性CD4 + CD25 + FoxP3 + T细胞的诱导，并与心脏同种异体移植排斥相关。同时，单细胞RNA测序和代谢分析显示，体内暴露于DST + CoB后cDC1线粒体代谢特征上调。cDC1线粒体代谢的基因失活降低了cDC1 TGF-β1的表达，减少了抗原特异性调节性T细胞群体，并损害了同种异体移植耐受。综上所述，我们的研究结果表明cDC1s参与了实体器官同种异体移植的保存策略，并且还表明cDC1s的线粒体代谢作为一种分子机制，通过TGF-β1增强抗原特异性CD4 + CD25 + FoxP3 + T细胞的生成。
