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

J Clin Invest. 2018 Oct 1;128(10):4557-4572. doi: 10.1172/JCI95914. Epub 2018 Sep 17.


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.

Keywords: Costimulation; Cytokines; Immunology; T cells; Transplantation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Graft Rejection / genetics
  • Graft Rejection / immunology*
  • Graft Rejection / pathology
  • Immunologic Memory*
  • Interleukin-15 / genetics
  • Interleukin-15 / immunology
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology
  • Interleukin-2 Receptor beta Subunit / genetics
  • Interleukin-2 Receptor beta Subunit / immunology*
  • Kidney Transplantation*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Receptors, Interleukin-2 / genetics
  • Receptors, Interleukin-2 / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*


  • Il2rb protein, mouse
  • Interleukin-15
  • Interleukin-2
  • Interleukin-2 Receptor beta Subunit
  • Receptors, Interleukin-2