IL-7 receptor blockade following T cell depletion promotes long-term allograft survival

Abstract

T cell depletion is commonly used in organ transplantation for immunosuppression; however, a restoration of T cell homeostasis following depletion leads to increased memory T cells, which may promote transplant rejection. The cytokine IL-7 is important for controlling lymphopoiesis under both normal and lymphopenic conditions. Here, we investigated whether blocking IL-7 signaling with a mAb that targets IL-7 receptor α (IL-7Rα) alone or following T cell depletion confers an advantage for allograft survival in murine transplant models. We found that IL-7R blockade alone induced indefinite pancreatic islet allograft survival if anti-IL-7R treatment was started 3 weeks before graft. IL-7R blockade following anti-CD4-and anti-CD8-mediated T cell depletion markedly prolonged skin allograft survival. Furthermore, IL-7 inhibition in combination with T cell depletion synergized with either CTLA-4Ig administration or suboptimal doses of tacrolimus to induce long-term skin graft acceptance in this stringent transplant model. Together, these therapies inhibited T cell reconstitution, decreased memory T cell numbers, increased the relative frequency of Tregs, and abrogated both cellular and humoral alloimmune responses. Our data suggest that IL-7R blockade following T cell depletion has potential as a robust, immunosuppressive therapy in transplantation.

Interleukin-27 promotes CD8+ T cell reconstitution following antibody-mediated lymphoablation

“…Given the critical importance of IL-7 signaling for T cell homeostatic proliferation in lymphopenic conditions (12, 15, 57, 58), our data strongly suggest that the reduced IL-7Rα expression may account for the observed reduction in CD8 + T cell reconstitution. These results are in consistence with previous reports that IL-7Rα blockade with mAb inhibited lymphocyte reconstitution following T cell depletion, thus prolonging skin allograft survival, and prevented graft-versus-host disease in a mouse model of allogeneic bone marrow transplantation (59,60). The results of the WT and IL-27R -/-CD8 + T cell cotransfer experiment demonstrate the direct effect of IL-27 on this lymphocyte population (Figure 8).…”

IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease

“…Finally, one potential advantage of IL-7Rα-targeted therapy is that it specifically spares Tregs over effector T cells (21), based on a high differential expression level (14,15). We found that IL-7 was able to dose-dependently induce STAT5 phosphorylation in Tregs, in spite of the low expression level of its receptor on these cells, but did not induce α 4 β 7 overexpression in contrast to its effect on effector T cells ( Figure 5D).…”

“…Human infants with IL-7Rα mutations have severe T cell lymphopenia necessitating bone marrow transplantation (82). In contrast to most studies performed in rodent models where IL-7R blockade also induces broad lymphodepletion (21), administration of high doses of anti-IL-7Rα antagonistic mAb in baboons (83), cynomolgus monkey (84), or marmosets (85) did not induce lymphopenia or a significant decrease in peripheral T lymphocyte numbers. Similarly, early clinical results from phase I trials with 2 different antagonist anti-IL-7Rα mAbs, in healthy volunteers (GSK2618960; NCT02293161, ClinicalTrials.gov) or in type 1 diabetic adult patients (PF-06342674; NCT02038764), did not demonstrate induction of lymphopenia (86).…”

“…Upon activation, IL-7R delivers proliferative and antiapoptotic signals by activating PI3K and JAK/STAT pathways as well as regulating expression of anti-and proapoptotic BCL-2 family members (19). More than 2 decades of research has reproducibly highlighted the crucial systemic influence of the IL-7 pathway and depicted IL-7 as a fuel for chronic autoimmune and inflammatory diseases as well as transplant rejection in diverse rodent models (20)(21)(22). Remarkably, the colon is the major source of IL-7 outside of the lymphoid tissues in mice, and commensal microflora promotes steady-state IL-7 production by intestinal epithelial cells (23,24).…”

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

“…In the context of islet transplantation, blocking IL-7Rα protected allogeneic islet grafts 126 from rejection in streptozotocin (STZ)-induced diabetic mice (Mai et al, 2014). Yet again, protection was associated with reduced T-cell IFN-γ production and PD-1 expression.…”