CD8 memory T cells rely on signaling through CD122, the shared IL-2 and IL-15 receptor β-chain. The addition of anti-CD122 to costimulation blockade prolongs graft survival, in part by controlling costimulation independent memory CD8 T cell expansion and effector function. Twelve Rhesus macaques underwent bilateral nephrectomy and life-sustaining renal transplantation using a kidney from an MHC-mismatched donor. Animals were treated with belatacept monotherapy, anti-CD122 monotherapy, or anti-CD122 + belatacept. For murine studies, congenically labeled TCR transgenic OT1 cells specific for Ovalbumin peptide were adoptively transferred to naïve B6 mice, who were infected with ova expressing listeria monocytogenes. Thirty days post-infection mice were given ova expressing skin grafts. For functional studies, mice were sacrificed at day 5 post skin graft and OT1 cells from spleen and draining lymph node were analyzed via flow cytometry. Rhesus kidney transplant recipients receiving combined CD122 and costimulation blockade enjoyed long term survival (MST=112 days) compared to animals treated with Belatacept alone (MST=29). In a murine model of memory CD8 T cell mediated rejection, combined CD122+costimulation blockade prolonged survival indefinitely (MST > 60 days) compared to costimulation blockade alone (MST = 20 days). Combined CD122 + costimulation blockade efficiently limits expansion and diminishes effector function of alloreactive CD8 memory T cells. The addition of therapies like anti-CD122 which target “costimulation-resistant” T cell subsets such memory T cells may allow for reduced rejection rates with belatacept-based therapy and encourage wider use in transplant recipients.

CITATION INFORMATION: Mathews D, Dong Y, Higginbotham L, Kim S, Breeden C, Tso J, Adams A. Combined CD122 and Costimulation Blockade Prolongs Allograft Survival by Controlling Expansion and Effector Function of Memory CD8 T Cells. Am J Transplant. 2016;16 (suppl 3).

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