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 4

Antigen-specific memory T cells do not require high-affinity IL-2R to mediate CoB resistant rejection.

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Antigen-specific memory T cells do not require high-affinity IL-2R to me...
(A) Utilizing the same model of memory CD8+ T cell mediated graft rejection as modeled in Figure 3, we evaluated the relative importance of the high-affinity IL-2 receptor by blocking CD25, compared with blocking CD122, which interrupts both the IL-2R and IL-15R. Untreated mice rejected rapidly (black triangle, MST = 11 days). CoB alone led to costimulation-independent rejection (black squares, MST = 16 days). Combined CoB+αCD25 (black diamonds, MST = 23 days) failed to prevent memory CD8+ T cell–mediated CoB-resistant rejection, whereas combined CoB+αCD122 resulted in indefinite graft survival in the majority of transplant recipients (black circles, MST > 100 days, P < 0.0001, n = 6–13 per group, Mantel-Cox log-rank test). (B) CoB+αCD122 synergistically controlled the expansion of antigen-specific CD8+ T cells during recall responses more effectively than CoB or CoB+αCD25 (P < 0.0001). (C) Representative FACS plot demonstrate reduced frequency of antigen-specific cells in CoB+αCD122-treated animals compared with CoB or CoB+αCD25. (D) CoB+αCD122 therapy resulted in a significant reduction of antigen-specific cells entering cell cycle, demonstrated by reduced Ki67 expression in representative histograms and the corresponding graph comparing CoB+αCD122 versus CoB or CoB+αCD25 (P = 0.0002). (E) In the BALB/c to C57BL/6 skin transplant model, a primary alloimmune challenge, the addition of αCD25 therapy (black squares), which interrupts the high-affinity IL-2R, demonstrated similar efficacy in prolonging allograft survival as the addition of αCD122 (black circles), which blocks both the IL-2R and IL-15R complexes. P values were generated by 1-way ANOVA followed by Bonferroni’s multiple comparisons test. Bars represent the mean ± SEM of 3–9 mice per group. Results are representative of 5 independent experiments. **P < 0.01, ****P < 0.0001.