CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection
David V. Mathews, … , Christian P. Larsen, Andrew B. Adams
David V. Mathews, … , Christian P. Larsen, Andrew B. Adams
Published September 17, 2018
Citation Information: J Clin Invest. 2018;128(10):4557-4572. https://doi.org/10.1172/JCI95914.
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Research Article Immunology

CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection

Abstract

Interrupting T cell costimulatory signals as a strategy to control undesired immune responses, such as occur in autoimmunity or transplantation, has the potential to alleviate many of the unwanted side effects associated with current immunosuppressive therapies. Belatacept, a high-affinity version of CTLA4-Ig that blocks ligand ligation to CD28, has been approved for use in kidney transplant recipients. Despite the long-term benefits associated with its use, such as improved renal function and lower cardiovascular risk, a subset of patients treated with belatacept experience elevated rates of acute T cell–mediated rejection, tempering enthusiasm for its use. Here we demonstrate that costimulation-independent T cell alloreactivity relies on signaling through CD122, the shared IL-2 and IL-15 receptor β-chain. Combined costimulatory and CD122 blockade improved survival of transplanted tissue in mice and nonhuman primates by controlling proliferation and effector function of CD8+ T cells. The high-affinity IL-2 receptor was dispensable for memory CD8+ T cell responses, whereas signaling through CD122 as a component of the high-affinity IL-15 receptor was critical for costimulation-independent memory CD8+ T cell recall, distinguishing specific roles for IL-2 and IL-15 in T cell activation. These studies outline a novel approach for clinical optimization of costimulatory blockade strategies in transplantation by targeting CD122.

Authors

David V. Mathews, Ying Dong, Laura B. Higginbotham, Steven C. Kim, Cynthia P. Breeden, Elizabeth A. Stobert, Joseph Jenkins, J. Yun Tso, Christian P. Larsen, Andrew B. Adams

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Figure 2

CD122 signaling underlies costimulation-independent rejection.

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CD122 signaling underlies costimulation-independent rejection. (A) Media...
(A) Median survival time (MST) of BALB/c skin allografts on C57BL/6 recipients without treatment was 10 days (black triangles, No Rx). Anti-CD122 alone failed to improve graft survival (open circles, MST = 10 days). Mice treated with CoB (CTLA4-Ig+αCD40L) succumb to costimulation-independent rejection (black squares, MST = 21 days). Combination CoB+αCD122 prolongs survival to greater than 80 days, preventing costimulation-independent rejection in the majority of recipients (n = 6–13 per group, representative of 3 independent experiments, P < 0.0001, Mantel-Cox log-rank test). (B) Mice were sacrificed at day 10 after transplant. Representative FACS plots of splenocytes from untreated (No Rx), CoB, and CoB+αCD122-treated animals. CoB+αCD122 resulted in reduced frequency of alloreactive CD44+CD122+ CD8+ T cells. Correspondingly, there is marked decrease in frequency of CD44+IFN-γ+ CD8+ T cells in both the spleen (P = 0.0048) and dLN (P = 0.0009), as well as a reduction in absolute numbers of alloreactive CD44+IFN-γ+ CD8+ T cells in the spleen (P = 0.0002) and dLN (P < 0.0001). (C) In a model of acute graft-versus-host disease, C57BL/6 splenocytes were labeled with CTV and transferred into sublethally irradiated BALB/c recipients, which were either untreated (No Rx), treated with CoB, or treated with CoB+αCD122. After 72 hours, splenocytes were harvested and assessed for CTV-labeled cell division as depicted in representative histograms. Both CD8+ (P < 0.0001) and CD4+ (P < 0.0001) alloproliferation was significantly constrained with combination CoB+αCD122 treatment. P values were generated by 1-way ANOVA followed by Tukey’s multiple comparisons test; bars represent the mean ± SEM of 3–5 mice per group (B–C). Results are representative of 3 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.