Interleukin-27 Enforces Regulatory T Cell Functions to Prevent Graft-versus-Host Disease

Abstract

Graft-versus-host disease (GvHD) remains a significant complication of allogeneic hematopoietic cell transplantation (HCT), associated with significant morbidity and mortality. GvHD is characterized by dysregulated immune responses and resulting tissue damage of target organs. Recent investigations have focused on Foxp3 + regulatory T cells (Tregs) as a therapeutic tool, based on its regulatory functions in GvHD pathogenesis and their instrumental role in mitigating GvHD severity while preserving graft-versus-leukemia (GvL) activity. There are several challenges to its clinical application, including their paucity, impaired suppressive activity, and instability in vivo. Herein, we report that IL-27 pre-stimulation enhances suppressive functions of both mouse and human Tregs. In a complete MHC mismatched murine bone marrow transplant model, IL-27 pre-stimulated polyclonal iTregs diminish acute (a)GvHD lethality, while preserving the GvL effect. Allo-antigen specificity further improves suppressive functions when combined with IL-27 pre-stimulation. In a xenogeneic (human to mouse) GvHD model, IL-27 pre-stimulated human iTregs are superior in protecting recipients from GvHD. Lastly, we compared gene expression profiles of circulating Tregs isolated from HCT recipients with and without aGvHD and found that Tregs from aGvHD patients express distinct gene signatures enriched in immune activation and inflammation. Therefore, these results highlight a novel function of IL-27 in enforcing Treg functions to prevent aGvHD mediated lethality, proposing the hypothesis that dysregulated Treg functions may account for the potential mechanisms underlying GvHD development.

Augmented expansion of Treg cells from healthy and autoimmune subjects via adult progenitor cell co-culture

“…The past decade has seen intense interest in evaluating the clinical utility of Tregs for a variety of indications including hematopoietic stem cell transplantation, autoimmune diseases and solid organ transplantation [3,27]. While the results from these initial clinical trials have demonstrated the potential therapeutic value of Tregs, isolation and expansion of Tregs is a major challenge due to reduced Treg frequencies and/or functionally defective Tregs reported in patients with autoimmune disorders [28][29][30][31][32][33][34]. In order to overcome this deficiency, a variety of ex vivo strategies have been developed to select, isolate and expand Tregs [4].…”

Newly Found Peacekeeper: Potential of CD8+ Tregs for Graft-Versus-Host Disease

“…Moreover, coadministration of anti-IL-27 and resiquimod, agonists of Toll-like receptor 7, increases the number of CD4 + and CD8 + Tregs and alleviates GVHD ( 81 ). Nevertheless, IL-27-primed CD4 + Tregs show immunoregulatory properties to provide a protective role in GVHD ( 82 ). IL-27 acts on multiple cells, including proinflammatory and regulatory cells and the final results depend on the overwhelming mechanism.…”

The immunomodulatory potentials of interleukin‐27 in airway allergies

“…In this regard, it has been shown that pre‐treatment of CD4 + CD25 + nTreg cells may potentize their anti‐proliferative effects on T cells 96 . Additionally, IL‐27 pretreated human iTregs are superior in protecting the recipients in the xenogenic Graft versus Host Disease (GvHD) model 97 . The conserved non‐coding sequence 2 (enhancer of FOXP3 locus) is hypermethylated in the case of induced Tregs than normally generated Tregs 98 .…”

“…xenogenic Graft versus Host Disease (GvHD) model. 97 The conserved non-coding sequence 2 (enhancer of FOXP3 locus) is hypermethylated in the case of induced Tregs than normally generated Tregs. 98 One could hypothesize that it may be possible that IL-27 stimulation may bring changes in the transcriptional landscape of Tregs which may control their effector profiles in case of allergies as observed with GvHD.…”