CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection
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
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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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 6

Humanized αCD122 synergizes with belatacept to inhibit alloreactivity and prolong NHP transplant survival.

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Humanized αCD122 synergizes with belatacept to inhibit alloreactivity an...
(A) MLR of NHP PBMCs between fully MHC-mismatched pairs. CFSE-labeled responder lymphocytes were incubated for 96 hours with irradiated stimulators (culture), with IL-15, IL-15+bela (belatacept), or IL-15+bela+αCD122. The addition of belatacept alone did not suppress proliferation, effector function, or loss of CD28 expression. The combination of bela+αCD122 reduced proliferation (P < 0.0001), diminished effector function (P = 0.0117), and restored CD28 expression on CD8+ T cells to similar levels as culture conditions without IL-15 (P = 0.8011). (B) Representative FACS plots of CD8+ T cell expansion by CFSE dilution, effector function as measured by dual IFN-γ and TNF production, and apoptosis and cell death as measured by 7-AAD and Annexin V staining (corresponds to graphs in A). (C) NHPs underwent bilateral nephrectomy and life-sustaining renal transplantation from a fully MHC-mismatched NHP donor. Animals were treated with humanized αCD122 alone (5 mg/kg, black circles, n = 2, MST = 7 days), belatacept alone (black squares, n = 5, MST = 29 days), or bela+αCD122 (black triangles, n = 5, MST = 138 days, P < 0.0001, Mantel-Cox log-rank test). Combination bela+αCD122 synergized to prolong NHP survival compared with belatacept monotherapy, or αCD122 monotherapy. (D) Corresponding serum creatinine curves of NHPs and demonstrated rejection were preceded by declining graft function. (A–B) P values were generated by repeat measures 1-way ANOVA and Tukey’s multiple comparisons test; bars represent the mean ± SEM of 3 NHPs per group. In vitro results are representative of 3 independent experiments. *P < 0.05; **P < 0.01.