Diversity of CD28^null T Cells in the Elderly: A Glimpse in a Biological Adaptation of Aging

Abstract

The age-dependent irreversible loss of CD28 is a unique property of the human immune system. Because CD28^null T cells have shortened telomeres and constitutively express high levels of mitotic inhibitors, these senescent cells have been argued to mediate the inefficiency of conventional clonotypic T cell receptor (TCR)-driven immunity among older adults. However, these CD28^null T cells are functionally active. Here, we review the diversity of these unusual cells, particularly in regard to their de novo expression of a wide array of receptors normally seen on natural killer cells. We will discuss their roles in driving TCR-independent immune effector function. Functionality of senescent CD28^null T cells illustrates the beneficial remodeling of the immune repertoire with aging. This concept is consistent with physiologic plasticity and with the broader Darwinian principle of biological adaptation . It is also in line with an emerging theme regarding the beneficial effects of cell senescence . We will discuss emerging evidence about the unique association of these T cells with maintenance of high-functional performance in late life. Integrating immune function, such as these novel CD28^null T cells, with cognitive and physical domains of function represents a new research frontier. Given the heterogeneity of health phenotypes of older adults, we propose that a research paradigm shift is paramount, namely, the analyses of defined populations of older adults, instead of continuing with the usual approach of young-versus-old comparison. This shift in research paradigm will be most instructive for innovations in age-appropriate, group-targeted immune interventions for the growing elderly population.