CD28(-) T cells: their role in the age-associated decline of immune function

Abstract

The accumulation of CD28(-) T cells, particularly within the CD8 subset, is one of the most prominent changes during T-cell homeostasis and function associated with aging in humans. CD28, a major co-stimulatory receptor, is responsible for the optimal antigen-mediated T-cell activation, proliferation and survival of T cells. CD28(-) T cells exhibit reduced antigen receptor diversity, defective antigen-induced proliferation and a shorter replicative lifespan while showing enhanced cytotoxicity and regulatory functions. Gene expression analyses reveal profound changes of CD28(-) T cells in comparison to their CD28(+) counterparts and corroborate their functional differences. Here we review recent advances in our understanding of CD28(-) T cells and their role in the age-associated decline of immune function.

Figure 1

Age associated accumulation of CD28⁻ T cells. A schematic presentation of the accumulation of CD28⁻ T cells with age for both CD4 and CD8 T cells. The ordinate indicates the frequency of CD28⁻ CD4 or CD28⁻ CD8 T cells. CD28⁻ CD8 T cells show a dramatic increase in number with age whereas the increase of CD28⁻ CD4 T cells is much more modest.

Figure 2

CD28⁻ T cell differentiation and functional changes. In vitro and probably in vivo, CD28⁻ T cells arise from CD28⁺ naïve and memory T cells (1) that have undergone repeated stimulation by antigen and/or by cytokines, particularly homeostatic cytokines (e.g IL-2, IL-7, IL-15). The differentiation path of CD28⁻ T cells can be further divided into two main stages based on the expression of CD45RA and CD27. Appropriate triggers (e.g. certain cytokines) might reverse the differentiation of CD45RA⁻CD28⁻CD27⁺ T cells (2) back to CD45RA⁺CD28⁺CD27⁺ T cells but CD45RA⁺CD28⁻CD27⁻ T cells (3) are considered to be terminally differentiated CD8 T cells. The antigen-induced proliferation of CD28⁻ T cells is profoundly impaired but their proliferative response to homeostatic cytokines appears normal. The acquisition of cytolytic function is one of the major features of CD28⁻ T cells and in addition immunoregulatory abilities have also been recently reported.