5 years ago

CD4+CD28null T Cells Are Not Alloreactive Unless Stimulated by IL-15

W Verschoor, R Kraaijeveld, C. C Baan, N. H. R Litjens, M. G. H Betjes, B Dedeoglu, M Klepper
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 by proliferation, degranulation, cytotoxicity and cytokine production. Furthermore, 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 IL-15 was added. However, they could proliferate upon stimulation with CMV-antigen without exogenous cytokines. IL-15 increased the frequency of proliferating alloreactive CD4+CD28null T cells to 30.5% without inducing CD28 expression (p<0.05). 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<0.001). Granzyme B and perforin positivity remained similar, but production of IFN-γ and TNF-α increased by the combination of IL-15 and IL-21 (p<0.001 and p<0.05, 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. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/ajt.14480

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