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

Abstract

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. (ClinicalTrials.gov - NCT00565773.).

CD69+ resident memory T cells are associated with graft-versus-host disease in intestinal transplantation

“…This further supports our hypothesis about the importance of effector memory cells during GvHD, since these cells would be expected to express such markers. 15,16,33,34 It also informs two important diagnostic and prognostic purposes. From a diagnostic perspective, the higher percentages of these markers could potentially serve as additional data points for diagnosing GvHD, a clinical diagnosis that can be difficult to make.…”

“…13,14 In rejection, its absence on antigen-experienced cells is associated with treatment resistance. 15,16 In certain types of cancer, one method by which tumor cells evade the host immune system is by expressing PD-L1 and PD-L2 to inhibit tumor-reactive host T cells, and, conversely, blocking the PD-1/PD-L1 pathway activates the antitumor response. 13 In GvHD after BMT, increased PD-1 expression within target host tissue at the time of GvHD is interpreted as increased graft T cells that have shifted from naïve to effector phenotype.…”

Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient

“…However, the risk of acute rejection, graft loss, and death were comparable [93,94] and despite the similar risk of graft and patient survival and less nephrotoxicity, widespread adoption of belatacept amongst all transplant recipients has been limited by concerns regarding higher rates of acute rejection and PTLD [95][96][97]. Subsequent to this, the understanding of the mechanisms of costimulation blockade resistant rejection (CoBRR) has improved [98][99][100][101]. Additionally, there is developing clinical evidence of significant dampening effects on humoral responses induced by costimulation blockade [90,91,102].…”

Age-related effects on thymic output and homeostatic T cell expansion following depletional induction in renal transplant recipients

“…IL-7 plays an important role in inducing CD57 − cell proliferation postdepletion. 11 Increased Ki67expressing cells postdepletion suggest homeostatic replication of T cells. Growing evidence suggests that DCs may play an important role in naïve and memory cell proliferation.…”

“…3,4,6,7 Lymphocyte reconstitution post-alemtuzumab induction is characterized by a rapid repopulation of CD27 − IgD + naïve B cells, 9 followed by slow T cell recovery. [6][7][8] Specifically, CD4 + cells repopulate with a CD28 + -enriched repertoire, a transient increase in CD4 + CD25 + Foxp3 + cells 6,8,10 and a reduction in CD57 + cells 11 -cells implicated in belatacept-resistant rejection. 12 Lymphocyte depletioninduced lymphopenia triggers T cell reconstitution through thymic output to generate T Naïve cells and homeostatic proliferation of residual peripheral cells 13 in patients' posttransplantation.…”