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 1

Kinetics of CD122 expression on CD8 T cells in acute viral infection and allograft rejection.

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Kinetics of CD122 expression on CD8 T cells in acute viral infection and...
(A) C57BL/6 mice were infected with LCMV Armstrong strain. The frequency and phenotype of antigen-specific (CD44+GP33 tetramer+) splenic CD8+ T cells were assessed longitudinally, and more than 95% of all antigen-specific T cells (black circles) expressed CD122 (gray squares). (B) The MFI of CD122 on antigen-specific T cells was highest at day 108 compared with day 8, P = 0.0002. (C) Representative FACS plot of data shown in A (top row) and B (middle row). Bottom row depicts changing phenotype of CD122+ cells after infection. (D) Representative histogram demonstrating that antigen-specific T cells are phenotypically CD127loKLRG1hi on day 8 after infection (unshaded) compared with a memory time point (day 108), when cells were CD127hiKLRG1lo (shaded). (E) CD122 is more highly expressed on antigen-specific TCM (CD44+CD62L+) CD8+ T cells compared with TEM (CD44+CD62L–) CD8+ T cells (P = 0.0274). (F) C57BL/6 (H2b) mice received BALB/c (H2d) skin grafts and were assessed longitudinally, similar to A. The majority of alloreactive CD8+CD44+ T cells (black circles) expressed CD122 (gray squares). (G) CD122 MFI was highest 100 days after transplant (P = 0.0011). (H) Representative FACS plot of data shown in F (top row) and G (middle row). Bottom row depicts phenotypic changes after transplant. (I) CD122+ cells demonstrate similar CD127 and KLRG1 expression at the peak of rejection (unshaded) and memory (shaded) compared with infection (D). (J) Alloreactive CD8+ TCM cells express higher levels of CD122 compared with TEM CD8+ T cells (P = 0.0016). P values generated by 1-way ANOVA with Tukey’s multiple comparisons test (B, G). Student’s t test, 2-tailed. Bars represent the mean ± SEM of 3 mice per group (E, J). All results, including FACS plots, represent 3 independent experiments (n = 3 mice/group). *P < 0.05; **P < 0.01; ***P < 0.001.