Regulation of CD28 expression on umbilical cord blood and adult peripheral blood CD8⁺ T cells by interleukin(IL)-15/IL-21

Interleukin (IL)-15 and IL-21, both belonging to common γ-chain-signaling cytokine family, have an important role to maintain homeostatic proliferation of CD8⁺ T cells. CD28, an essential co-stimulatory molecule on T cells, may be a marker of replicative senescence. We investigated the effect of IL-15 and IL-21, alone or in combination, on activation, apoptosis, cytokine production and cytotoxic function of magnetic bead purified umbilical cord blood (UCB) and adult peripheral blood (APB) CD8⁺ T cells with regards to their CD28 expression. We established that (1) IL-15-induced CD8⁺ T cell proliferation was associated with a preferential expansion of CD28^- population in UCB, which could be partially counteracted by IL-21; (2) UCB CD8⁺ T cells were more readily responsive to IL-15 compared to their adult counterparts in terms of CD69 expression, with the majority of CD69-bearing CD8⁺ T cells were CD28^-; (3) IL-21 further promoted interferon-gamma, but not tumor necrosis factor-alpha production from IL-15 treated CD8⁺ T cells; (4) IL-21 also synergized with IL-15 to enhance perforin and granzyme B expression of CD8⁺ T cells, especially in APB CD8⁺CD28^- subsets; (5) IL-21 resulted in CD8⁺ T cells apoptosis both in APB and UCB cells, mainly in CD8⁺CD28^- subsets. Taken together, we demonstrate differential IL-15/IL-21 response in UCB CD8⁺ T cells with regards to CD28 expression. Our results suggest that combining IL-21 and IL-15 immunotherapy may be better than IL-15 alone to ameliorate graft-versus-host disease while preserving antitumor effect in the post-UCB transplantation period.