Background & Study Aim. We recently showed that an accumulation of highly differentiated TEMRA CD8 T cells in kidney transplant recipients with a stable graft function is associated with an increased risk of kidney graft dysfunction. These observations are controversial with data from the literature reporting that differentiated TEMRA CD8 T cells are associated with senescent cells. Because CD8 T cell response regulation is important for the rational design of immune-based strategies to treat transplant recipients, we aimed to identify signaling pathways involved in regulation of the survival and the activation of TEMRA CD8 T cells.

Method. Susceptibility of TEMRA to cytokine (IL-2/7/15) stimulation was screened using phospho-mAbs. Cytokines and TCR were added alone or in combination to purified naïve (CD45RA⁺CD28⁺), TEMRA (CD45RA⁺CD28^–) and EM early (CD45RA^–CD28⁺) CD8 T cells. Survival (DAPI), proliferation (Cell Fluorescent Dye), activation (CD25 and CD69) were monitored. Signaling pathways were interrogated by the provision of mTOR, p38 MAPK and ERK inhibitors. Finally, modification of mitochondrial membrane potential was assessed using MitoTracker Red and JC-1.

Results. TEMRA CD8 efficiently responds to short-term stimulation with IL-2 and IL-15 as shown by the phosphorylation of STAT5 and S6 Kinase. IL-2 and IL-15 but not IL-7 nor TCR stimulation alone are able to prevent TEMRA CD8 cell death, by preventing the depolarization of the mitochondrial membrane potential. Whereas inhibition of mTOR does not alter the pro-survival signal from IL-2 or IL-15, inhibition of p38MAPK and Erk blunts this beneficial signal. In combination with TCR signals, IL-2 and IL-15 are able to efficiently activate TEMRA CD8 as shown by cell proliferation and upregulation of CD25 and CD69.

Conclusion. In contrast to their view as senescent cells, we provide evidences that TEMRA CD8 shares similar regulation of survival and function with EM cells when stimulated with IL-2 and/or IL-15, two instrumental cytokines involved in CD8 T cell regulation. These data emphasize the need to re-assess their pathogenic role in the context of transplantation.

CITATION INFORMATION: Tilly G, Yap M, Giral M, Pecqueur C, Brouard S, Degauque N. IL2 and IL-15 Rescue TEMRA CD8 T Cells from Mitochondrial Dysfunction Associated Senescence Through a p38MAPK Dependent Pathway and Foster Their Pathogenic Potential. Am J Transplant. 2016;16 (suppl 3).

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