The hallmarks of CMV-specific CD8 T-cell differentiation

Abstract

Upon cytomegalovirus (CMV) infection, large T-cell responses are elicited that remain high or even increase over time, a phenomenon named memory T-cell inflation. Besides, the maintained robust T-cell response, CMV-specific T cells seem to have a distinctive phenotype, characterized by an advanced differentiation state. Here, we will review this "special" differentiation status by discussing the cellular phenotype based on the expression of CD45 isoforms, costimulatory, inhibitory and natural killer receptors, adhesion and lymphocyte homing molecules, transcription factors, cytokines and cytotoxic molecules. In addition, we focus on whether the differentiation state of CMV-specific CD8 T cells is unique in comparison with other chronic viruses and we will discuss the possible impact of factors such as antigen exposure and aging on the advanced differentiation status of CMV-specific CD8 T cells.

Targeted in-vitro-stimulation reveals highly proliferative multi-virus-specific human central memory T cells as candidates for prophylactic T cell therapy

“…We used this same clinical grade T CM product to look also for the expression of available co-inhibitory markers (PD-1, TIM-3 and LAG-3) on proliferated virus-specific T cells. Those markers can be sign of T cell exhaustion after continuous antigen stimulation, while In particular PD-1 expression can be also influenced by the activation and differentiation state of the analyzed T cells [48,49]. We found an intermediate PD-1 expression on roughly 50% of CMV- and EBV-peptide-specific CD8 + T cells after proliferation in PSPA.…”

“…PD-1 hi T cells, which are associated with an irreversible dysfunctional state [65], were exclusively found on MHC multimer-negative T cells. In particular expression of PD-1 could be also influenced by the activation and differentiation state of the analyzed T cells [48,49]. Activated T cells can transiently express PD-1, expression on intermediate differentiation states (T EM ) of virus-specific CD8 + T cells was also found [66,67].…”

SARS-CoV-2-Specific T Cells Exhibit Phenotypic Features of Helper Function, Lack of Terminal Differentiation, and High Proliferation Potential

“… 39 These cells have been shown to be protective against a variety of viral pathogens, including CMV, the flu, Epstein-Barr virus (EBV), and Human Immunodeficiency Virus (HIV). 40 , 41 , 42 , 43 Exceptionally high numbers of CMV-specific Temra cells have been observed in CMV-infected individuals, 44 and this subset also constitutes a major proportion of dengue-specific CD8+ T cells in individuals that have recovered from dengue infection. 45 , 46 Although generally thought to be terminally differentiated, some CD8+ Temra cells can be long-lived.…”

How age and infection history shape the antigen‐specific CD8+ T‐cell repertoire: Implications for vaccination strategies in older adults

“…The virus is thought to frequently reactivate, leading to restimulation of the anti-CMV immune response. Hallmarks of CMV infection are the presence of clonal expansions and large numbers of highly differentiated cells in the CD8 + T-cell memory pool (van den Berg et al, 2019). These clonal expansions are often directed to the pp65 protein and can be focused on only one or a small number of epitopes, like the HLA-A2 restricted NLVPMVATV (A2-NLV) epitope.…”