IL-7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade-resistant rejection

Am J Transplant. 2018 Mar;18(3):720-730. doi: 10.1111/ajt.14589. Epub 2017 Dec 12.


Kidney transplant patients treated with belatacept without depletional induction experience higher rates of acute rejection compared to patients treated with conventional immunosuppression. Costimulation blockade-resistant rejection (CoBRR) is associated with terminally differentiated T cells. Alemtuzumab induction and belatacept/sirolimus immunotherapy effectively prevent CoBRR. We hypothesized that cells in late phases of differentiation would be selectively less capable than more naive phenotypes of repopulating postdepletion, providing a potential mechanism by which lymphocyte depletion and repopulation could reduce the risk of CoBRR. Lymphocytes from 20 recipients undergoing alemtuzumab-induced depletion and belatacept/sirolimus immunosuppression were studied longitudinally for markers of maturation (CCR7, CD45RA, CD57, PD1), recent thymic emigration (CD31), and the IL-7 receptor-α (IL-7Rα). Serum was analyzed for IL-7. Alemtuzumab induction produced profound lymphopenia followed by repopulation, during which naive IL-7Rα+ CD57- PD1- cells progressively became the predominant subset. This did not occur in a comparator group of 10 patients treated with conventional immunosuppression. Serum from depleted patients showed markedly elevated IL-7 levels posttransplantation. Sorted CD57- PD1- cells demonstrated robust proliferation in response to IL-7, whereas more differentiated cells proliferated poorly. These data suggest that differences in IL-7-dependent proliferation is one exploitable mechanism that distinguishes CoB-sensitive and CoB-resistant T cell populations to reduce the risk of CoBRR. ( - NCT00565773.).

Keywords: basic (laboratory) research/science; clinical research/practice; cytokines/cytokine receptors; immunobiology; immunosuppressant - fusion proteins and monoclonal antibodies: belatacept; immunosuppressant - mechanistic target of rapamycin: sirolimus; immunosuppression/immune modulation; immunosuppressive regimens - induction; kidney transplantation/nephrology; lymphocyte biology: differentiation/maturation.

Publication types

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

MeSH terms

  • Abatacept / pharmacology*
  • CD57 Antigens / metabolism
  • Cell Proliferation*
  • Graft Rejection / etiology
  • Graft Rejection / metabolism
  • Graft Rejection / prevention & control*
  • Graft Survival / drug effects
  • Graft Survival / immunology*
  • Humans
  • Immunologic Memory
  • Immunosuppressive Agents / pharmacology
  • Interleukin-7 / metabolism*
  • Kidney Transplantation*
  • Lymphocyte Depletion*
  • Prognosis
  • Receptors, Interleukin-7 / classification
  • Receptors, Interleukin-7 / metabolism*
  • Risk Factors


  • CD57 Antigens
  • Immunosuppressive Agents
  • Interleukin-7
  • Receptors, Interleukin-7
  • interleukin-7 receptor, alpha chain
  • Abatacept

Associated data