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 3

CD122 signaling supports costimulation-independent recall responses.

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CD122 signaling supports costimulation-independent recall responses. (A)...
(A) In a model of memory CD8+ T cell–mediated graft rejection, OVA-specific CD8+ T cells (Thy1.1+OT-1) were transferred into naive C57BL/6 mice. Mice were immunized 24–48 hours later with Listeria monocytogenes expressing ovalbumin (Lm.OVA). After 30 days, mice were challenged with an OVA-expressing skin graft. (B) Untreated mice experienced rapid acute rejection (black triangles, No Rx, MST = 11). Mice treated with αCD122 rejected their skin grafts with similar kinetics to untreated mice (black diamonds, αCD122, MST = 13). CoB treated mice experienced memory CD8+ T cell mediated costimulation independent rejection shortly after (black squares, CoB, MST=16). Addition of αCD122 synergized with CoB to prolong graft survival indefinitely (black circles, CoB+αCD122, MST > 100 days, n = 6–13/group, P < 0.0001 Mantel-Cox log-rank test). (C) We investigated the impact of CoB+αCD122 by examining the frequency and function of graft specific CD8+ T cells in the draining lymph nodes 5 days after transplantation. Addition of αCD122 constrains the expansion of graft specific CD8+ T cells as demonstrated in representative FACS plots. (D) Both absolute number of graft specific (Thy1.1+) cells (P < 0.0001) and IFN-γ+ cells (P < 0.0001) were diminished with the addition of αCD122. (E) CoB+αCD122 therapy resulted in increased coinhibitory receptor expression on remaining graft specific CD8+ T cells. Thy1.1+ cells demonstrated increased PD-1 (P = 0.0303) and CTLA4 (P = 0.0065) expression. Additionally, decreased Ki67 expression (P = 0.0250) indicated reduced cell-cycle entry. (C–E) P values were generated by 1-way ANOVA followed by Bonferroni’s multiple comparisons test. Bars represent the mean ± SEM of 3–7 mice per group. Results are representative of 5 independent experiments. *P < 0.05; ***P < 0.001; ****P < 0.0001.