CD4+CD28null T cells are not alloreactive unless stimulated by interleukin-15

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.

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