Department of Medicine, Nephrology, Stanford University, Palo Alto, CA, United States.
Macaulay Honors College, Hunter College, The City University of New York, New York, NY, United States.
Front Immunol. 2022 Jun 28;13:904705. doi: 10.3389/fimmu.2022.904705. eCollection 2022.
Cytomegalovirus (CMV) infection is a known cause of morbidity and mortality in solid organ transplant recipients. While primary infection is controlled by a healthy immune system, CMV is never eradicated due to viral latency and periodic reactivation. Transplantation and associated therapies hinder immune surveillance of CMV. CD4 T cells are an important part of control of CMV reactivation. We therefore investigated how CMV impacts differentiation, functionality, and expansion of protective CD4 T cells from recipients of heart or kidney transplant in the first year post-transplant without evidence of CMV viremia. We analyzed longitudinal peripheral blood samples by flow cytometry and targeted single cell RNA sequencing coupled to T cell receptor (TCR) sequencing. At the time of transplant, CD4 T cells from CMV seropositive transplant recipients had a higher degree of immune aging than the seronegative recipients. The phenotype of CD4 T cells was stable over time. CMV-responsive CD4 T cells in our transplant cohort included a large proportion with cytotoxic potential. We used sequence analysis of TCRαβ to identify clonal expansion and found that clonally expanded CMV-responsive CD4 T cells were of a predominantly aged cytotoxic phenotype. Overall, our analyses suggest that the CD4 response to CMV is dominated by cytotoxicity and not impacted by transplantation in the first year. Our findings indicate that CMV-responsive CD4 T cells are homeostatically stable in the first year after transplantation and identify subpopulations relevant to study the role of this CD4 T cell population in post-transplant health.
巨细胞病毒（CMV）感染是实体器官移植受者发病率和死亡率的已知原因。虽然原发性感染可被健康的免疫系统所控制，但由于病毒潜伏和周期性激活，CMV 永远无法被根除。移植和相关治疗会阻碍 CMV 的免疫监测。CD4 T 细胞是控制 CMV 再激活的重要组成部分。因此，我们研究了在无 CMV 病毒血症证据的情况下，移植后第一年心脏或肾脏移植受者的 CMV 如何影响保护性 CD4 T 细胞的分化、功能和扩增。我们通过流式细胞术和靶向单细胞 RNA 测序结合 T 细胞受体（TCR）测序分析了纵向外周血样本。在移植时，CMV 血清阳性移植受者的 CD4 T 细胞的免疫衰老程度高于血清阴性受者。CD4 T 细胞的表型随时间保持稳定。我们移植队列中的 CMV 反应性 CD4 T 细胞包括很大一部分具有细胞毒性潜能。我们使用 TCRαβ 的序列分析来识别克隆扩增，并发现克隆扩增的 CMV 反应性 CD4 T 细胞主要具有衰老的细胞毒性表型。总的来说，我们的分析表明，CD4 对 CMV 的反应主要由细胞毒性主导，而在移植后的第一年不受其影响。我们的研究结果表明，移植后第一年 CMV 反应性 CD4 T 细胞在体内处于稳定状态，并确定了与研究该 CD4 T 细胞群体在移植后健康中的作用相关的亚群。
