Department of Microbiology and Immunology, University of California, San Francisco, CA 94143.
Parker Institute for Cancer Immunotherapy, University of California, San Francisco, CA 94143.
Proc Natl Acad Sci U S A. 2022 Feb 22;119(8). doi: 10.1073/pnas.2116588119.
Cytomegalovirus (CMV) infection is associated with graft rejection in renal transplantation. Memory-like natural killer (NK) cells expressing NKG2C and lacking FcεRIγ are established during CMV infection. Additionally, CD8 T cells expressing NKG2C have been observed in some CMV-seropositive patients. However, in vivo kinetics detailing the development and differentiation of these lymphocyte subsets during CMV infection remain limited. Here, we interrogated the in vivo kinetics of lymphocytes in CMV-infected renal transplant patients using longitudinal samples compared with those of nonviremic (NV) patients. Recipient CMV-seropositive (R+) patients had preexisting memory-like NK cells (NKG2CCD57FcεRIγ) at baseline, which decreased in the periphery immediately after transplantation in both viremic and NV patients. We identified a subset of prememory-like NK cells (NKG2CCD57FcεRIγ) that increased during viremia in R+ viremic patients. These cells showed a higher cytotoxic profile than preexisting memory-like NK cells with transient up-regulation of FcεRIγ and Ki67 expression at the acute phase, with the subsequent accumulation of new memory-like NK cells at later phases of viremia. Furthermore, cytotoxic NKG2CCD8 T cells and γδ T cells significantly increased in viremic patients but not in NV patients. These three different cytotoxic cells combinatorially responded to viremia, showing a relatively early response in R+ viremic patients compared with recipient CMV-seronegative viremic patients. All viremic patients, except one, overcame viremia and did not experience graft rejection. These data provide insights into the in vivo dynamics and interplay of cytotoxic lymphocytes responding to CMV viremia, which are potentially linked with control of CMV viremia to prevent graft rejection.
巨细胞病毒（CMV）感染与肾移植中的移植物排斥反应有关。在 CMV 感染期间，会建立表达 NKG2C 且缺乏 FcεRIγ的记忆样自然杀伤（NK）细胞。此外，在一些 CMV 血清阳性患者中也观察到表达 NKG2C 的 CD8 T 细胞。然而，CMV 感染期间这些淋巴细胞亚群的体内动力学发展和分化仍有限。在这里，我们通过纵向样本比较，探究了 CMV 感染的肾移植受者体内淋巴细胞的体内动力学。与非病毒血症（NV）患者相比，CMV 血清阳性（R+）患者在基线时就存在预先存在的记忆样 NK 细胞（NKG2CCD57FcεRIγ），这些细胞在病毒血症和 NV 患者移植后立即在外周减少。我们鉴定了一个亚群的前记忆样 NK 细胞（NKG2CCD57FcεRIγ），在 R+病毒血症患者的病毒血症期间增加。这些细胞表现出更高的细胞毒性特征，与预先存在的记忆样 NK 细胞相比，其在急性期短暂上调 FcεRIγ和 Ki67 表达，随后在病毒血症的后期阶段积累新的记忆样 NK 细胞。此外，病毒血症患者的细胞毒性 NKG2CCD8 T 细胞和γδ T 细胞显著增加，而 NV 患者则没有。这三种不同的细胞毒性细胞组合性地对病毒血症作出反应，与 R+病毒血症患者相比，R-病毒血症患者的反应相对较早。除了一名患者外，所有病毒血症患者均克服了病毒血症且未发生移植物排斥反应。这些数据提供了对细胞毒性淋巴细胞对 CMV 病毒血症反应的体内动力学和相互作用的深入了解，这可能与控制 CMV 病毒血症以预防移植物排斥反应有关。
