Single‐cell transcriptomic and T cell antigen receptor analysis of human cytomegalovirus (hCMV)‐specific memory T cells reveals effectors and pre‐effectors of CD8+‐ and CD4+‐cytotoxic T cells

Abstract

AbstractLatent human cytomegalovirus (hCMV) infection can pose a serious threat of reactivation and disease occurrence in immune‐compromised individuals. Although T cells are at the core of the protective immune response to hCMV infection, a detailed characterization of different T cell subsets involved in hCMV immunity is lacking. Here, in an unbiased manner, we characterized over 8000 hCMV‐reactive peripheral memory T cells isolated from seropositive human donors, at a single‐cell resolution by analysing their single‐cell transcriptomes paired with the T cell antigen receptor (TCR) repertoires. The hCMV‐reactive T cells were highly heterogeneous and consisted of different developmental and functional memory T cell subsets such as, long‐term memory precursors and effectors, T helper‐17, T regulatory cells (TREGs) and cytotoxic T lymphocytes (CTLs) of both CD4 and CD8 origin. The hCMV‐specific TREGs, in addition to being enriched for molecules known for their suppressive functions, showed enrichment for the interferon response signature gene sets. The hCMV‐specific CTLs were of two types, the pre‐effector‐ and effector‐like. The co‐clustering of hCMV‐specific CD4‐CTLs and CD8‐CTLs in both pre‐effector as well as effector clusters suggest shared transcriptomic signatures between them. The huge TCR clonal expansion of cytotoxic clusters suggests a dominant role in the protective immune response to CMV. The study uncovers the heterogeneity in the hCMV‐specific memory T cells revealing many functional subsets with potential implications in better understanding of hCMV‐specific T cell immunity. The data presented can serve as a knowledge base for designing vaccines and therapeutics.