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

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- (IL-7R). Serum was analyzed for IL-7. Alemtuzumab induction produced profound lymphopenia followed by repopulation, during which naive IL-7R(+)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. (ClinicalTrials.gov - NCT00565773.) Patients treated with alemtuzumab induction followed by a belatacept-based immunosuppressive regimen repopulate predominantly with IL-7R+CD57-PD1- cells, and the difference in IL-7-dependent proliferation is one exploitable mechanism distinguishing costimulation blockade-sensitive and -resistant T cells in reducing the risk of costimulationresistant rejection.