CD57-Expressing Lymphocytes: From Chronic Viral Response to Age-Related Inflammation

Abstract

Highlights: What are the main findings? CD57 marks advanced differentiation across T and NK cells, but CD57+ CD4+ and CD57+ CD8+ T cells show distinct developmental trajectories and functional programs rather than a uniform senescent state. CMV-driven chronic stimulation is the dominant force shaping CD57+ lymphocyte expansion, linking viral persistence with cytotoxic specialization and immune remodelling. What are the implications of the main findings? CD57 should be interpreted as a context-dependent differentiation and immune-history marker—not a direct therapeutic target—and CD57+ CD4+ and CD57+ CD8+ subsets must be analyzed separately. Proper interpretation of CD57+ subsets, with CMV stratification, improves immune profiling in aging, chronic infection, cardiovascular and autoimmune disease, cancer, and vaccine-response studies. CD57-expressing lymphocytes constitute a distinct subset of immune cells with enhanced cytotoxic and pro-inflammatory functions. Initially described in the context of chronic viral infections, most notably cytomegalovirus (CMV), these cells are now recognized as central contributors to immunosenescence and age-related immune dysregulation. Their progressive accumulation reflects prolonged antigenic exposure and sustained immune activation, thereby linking persistent viral infections with long-term disruptions of immune homeostasis. Emerging evidence indicates that CD57 expression denotes a state of terminal differentiation in both T and natural killer (NK) cell compartments, and is associated with cytotoxicity, altered cytokine secretion, and a pro-inflammatory phenotype. This review summarizes the phenotypic and functional characteristics of CD57+ lymphocytes, examines their association with CMV and other chronic viral infections, and explores their potential role in ageing and age-related diseases. Elucidating the biology of CD57+ lymphocytes in the context of chronic viral infections may provide novel insights into immune ageing and help identify potential targets for therapeutic strategies aimed at restoring immune balance in older adults.