Cytotoxic CD4+ T cells across aging: a conceptual framework for health, protection, pathology, and age-associated diseases

Aging is the primary risk factor for a wide spectrum of chronic diseases, ranging from infectious diseases and cancer to autoimmunity and neurodegeneration. One of the key drivers of this increased susceptibility is the progressive decline in immune function-immunosenescence that reshapes the host's inflammatory landscape. Emerging evidence points to an age-associated expansion of cytotoxic CD4+ T cells (CD4 CTLs), which can play context-dependent protective or pathogenic roles in host homeostasis and disease, reflecting their unique integration of helper and cytotoxic programs as well as their preferential expansion during aging. On the protective side, CD4 CTLs contribute to immune surveillance and host defense against viral infections and malignancies. Conversely, in selected settings, they can function as pathogenic effectors in autoimmune and neurodegenerative disorders. In this review, we synthesize the emerging biology of CD4 CTLs, highlighting their differentiation and dual roles in protection and pathology. Beyond a descriptive overview, we propose a conceptual framework that places age-associated CD4 CTL expansion at the intersection of aging and age-associated disease. Rather than viewing late-life pathologies as fully independent events, we suggest that at least a subset may be partially interconnected by recurrent CD4 CTL programs, while emphasizing that the strength of evidence and the degree of causality differ substantially by disease context. This framework provides a basis for asking when CD4 CTLs should be enhanced, restrained, or more precisely redirected to promote healthy longevity.