CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28−CD8+ T Cells

A substantial proportion of CD8+ T cells in adults lack the expression of the CD28 molecule, and the aging of the immune system is associated with a steady expansion of this T cell subset. CD28−CD8+ T cells are characterized by potent effector functions but impaired responses to antigenic challenge. CD28 acts as the primary T cell costimulatory receptor, but there are numerous additional receptors that can costimulate the activation of T cells. In this study, we have examined such alternative costimulatory pathways regarding their functional role in CD28−CD8+ T cells. Our study showed that most costimulatory molecules have a low capacity to activate CD28-deficient T cells, whereas the engagement of the CD2 molecule by its ligand CD58 clearly costimulated proliferation, cytokine production, and effector function in this T cell subset. CD58 is broadly expressed on APCs including dendritic cells. Blocking CD58 mAb greatly reduced the response of human CD28−CD8+ T cells to allogeneic dendritic cells, as well as to viral Ags. Our results clearly identify the CD58/CD2 axis as the primary costimulatory pathway for CD8 T cells that lack CD28. Moreover, we show that engagement of CD2 amplifies TCR signals in CD28−CD8+ T cells, demonstrating that the CD2–CD58 interaction has a genuine costimulatory effect on this T cell subset. CD2 signals might promote the control of viral infection by CD28−CD8+ T cells, but they might also contribute to the continuous expansion of CD28−CD8+ T cells during chronic stimulation by persistent Ag.