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

Cytokine. 2012 Apr;58(1):40-6. doi: 10.1016/j.cyto.2011.12.013. Epub 2012 Jan 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apoptosis / drug effects
  • CD28 Antigens / biosynthesis*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / metabolism*
  • Down-Regulation / drug effects
  • Female
  • Fetal Blood / cytology*
  • Fetal Blood / drug effects
  • Graft vs Host Disease
  • Granzymes / biosynthesis
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-15 / pharmacology*
  • Interleukins / pharmacology*
  • Perforin / biosynthesis
  • Pregnancy
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Up-Regulation


  • CD28 Antigens
  • Interleukin-15
  • Interleukins
  • Tumor Necrosis Factor-alpha
  • Perforin
  • Interferon-gamma
  • Granzymes
  • interleukin-21