Nantes Université, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, Nantes, France.
CHU Nantes, Nantes Université, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, France.
Front Immunol. 2022 Dec 1;13:1063690. doi: 10.3389/fimmu.2022.1063690. eCollection 2022.
The human cytomegalovirus (HCMV) triggers both innate and adaptive immune responses, including protective CD8 αβT cells (CD8T) that contributes to the control of the infection. In addition to CD8T restricted by classical HLA class Ia molecules, HCMV also triggers CD8T recognizing peptides from the HCMV UL40 leader peptide and restricted by HLA-E molecules (HLA-E CD8T). This study investigated the frequency, phenotype and functions of HLA-E CD8T in comparison to the immunodominant HLA-A2 CD8T upon acute (primary or secondary infection) or chronic infection in kidney transplant recipients (KTR) and in seropositive (HCMV) healthy volunteer (HV) hosts. The frequency of hosts with detected HLA-E CD8T was similar after a primary infection (24%) and during viral latency in HCMV+ HV (26%) and equal to the frequency of HLA-A2 CD8T cells in both conditions (29%). Both CD8T subsets vary from 0.1% to >30% of total circulating CD8T according to the host. Both HLA-E and HLA-A2 CD8T display a phenotype specific of CD8 TEMRA (CD45RA/CCR7) but HLA-E CD8T express distinctive level for CD3, CD8 and CD45RA. Tim3, Lag-3, 4-1BB, and to a lesser extend 2B4 are hallmarks for T cell priming post-primary infection while KLRG1 and Tigit are markers for restimulated and long lived HCMV-specific CD8T responses. These cell markers are equally expressed on HLA-E and HLA-A2 CD8T. In contrast, CD56 and PD-1 are cell markers discriminating memory HLA-E- from HLA-A2-restricted CD8T. Long lived HLA-E display higher proliferation rate compared to HLA-A2 CD8T consistent with elevated CD57 expression. Finally, a comparative immunoprofiling indicated that HLA-E CD8T, divergent from HLA-A2 CD8T, share the expression of CD56, CD57, NKG2C, CD158 and the lack of PD-1 with NKG2CCD57+ NK and δ2γδT cells induced in response to HCMV and thus defines a common immunopattern for these subsets.
人巨细胞病毒 (HCMV) 触发先天和适应性免疫反应，包括保护性 CD8αβT 细胞 (CD8T)，有助于控制感染。除了受经典 HLA 类 I 分子限制的 CD8T 外，HCMV 还触发识别来自 HCMV UL40 前导肽的肽并受 HLA-E 分子限制的 CD8T (HLA-E CD8T)。本研究比较了急性 (原发性或继发性感染) 或慢性感染的肾移植受者 (KTR) 和血清阳性 (HCMV) 健康志愿者 (HV) 中 HLA-E CD8T 与免疫优势 HLA-A2 CD8T 的频率、表型和功能。在原发性感染后 (24%) 和 HCMV+HV 病毒潜伏期期间，检测到 HLA-E CD8T 的宿主频率相似 (26%)，与两种情况下 HLA-A2 CD8T 细胞的频率相等 (29%)。根据宿主的不同，这两个 CD8T 亚群的频率在 0.1%到 >30%的总循环 CD8T 之间变化。HLA-E 和 HLA-A2 CD8T 均表现出 CD8 TEMRA (CD45RA/CCR7) 的表型特异性，但 HLA-E CD8T 对 CD3、CD8 和 CD45RA 的表达具有独特的水平。Tim3、Lag-3、4-1BB，在较小程度上还有 2B4，是原发性感染后 T 细胞启动的标志，而 KLRG1 和 Tigit 是重新刺激和长期存在的 HCMV 特异性 CD8T 反应的标志物。这些细胞标志物在 HLA-E 和 HLA-A2 CD8T 上同样表达。相比之下，CD56 和 PD-1 是区分记忆 HLA-E-和 HLA-A2 限制的 CD8T 的细胞标志物。与 HLA-A2 CD8T 相比，长期存在的 HLA-E 表现出更高的增殖率，这与 CD57 表达的升高一致。最后，比较免疫分析表明，与 HLA-A2 CD8T 不同，HLA-E CD8T 共享 CD56、CD57、NKG2C、CD158 的表达，以及缺乏 PD-1，与 HCMV 诱导的 NKG2CCD57+NK 和 δ2γδT 细胞相同，因此为这些亚群定义了一个共同的免疫模式。
