Proinflammatory, cytotoxic CD4+CD28null T cells can be substantially expanded in patients with end-stage renal disease. These cells have been associated with the risk for rejection, but their alloreactive potential is unknown. CD4+CD28null T cells were stimulated with HLA-mismatched antigen presenting cells in the absence/presence of exogenous cytokines. Alloreactive potential was evaluated based on proliferation, degranulation, cytotoxicity, and cytokine production. Further, their suppressive capacity was assessed by measuring inhibition of proliferating alloreactive CD28+ T cells. CD4+CD28null T cells contained alloreactive (CD137+) T cells but did not proliferate in response to allogeneic stimulation, unless interleukin (IL)-15 was added. However, they could proliferate on stimulation with cytomegalovirus antigen without exogenous cytokines. IL-15 increased the frequency of proliferating alloreactive CD4+CD28null T cells to 30.5% without inducing CD28 expression (P <.05). After allogeneic stimulation together with IL-15 and IL-21, frequency of degranulating CD107a+CD4+CD28null T cells increased significantly from 0.6% to 5.8% (P <.001). Granzyme B and perforin positivity remained similar, but production of interferon-γ and tumor necrosis factor-α increased by the combination of IL-15 and IL-21 (P <.001 and P <.05, respectively). Finally, CD4+CD28null T cells did not show significant suppression. Thus, CD4+CD28null T cells represent a population with absent alloreactivity unless IL-15 is present.

Additional Metadata
Keywords alloantigen, basic (laboratory) research/science, immunobiology, immunosuppression/immune modulation, kidney transplantation/nephrology, T cell biology
Persistent URL dx.doi.org/10.1111/ajt.14480, hdl.handle.net/1765/112459
Journal American Journal of Transplantation
Citation
Dedeoğlu, B, Litjens, N.H.R, Klepper, M, Kraaijeveld, R, Verschoor, W, Baan, C.C, & Betjes, M.G.H. (2018). CD4+CD28null T cells are not alloreactive unless stimulated by interleukin-15. American Journal of Transplantation, 18(2), 341–350. doi:10.1111/ajt.14480