Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD

Abstract

• Acute GVHD leads to defective MHC class II antigen presentation by donor DC, leading to a failure of peripheral Treg homeostasis.• Impaired Treg homeostasis results in chronic GVHD directly and can be alleviated by adoptive Treg transfer.Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD. (Blood. 2016;128(6):794-804)

Chronic graft-versus-host disease: biological insights from preclinical and clinical studies

“…127,128,146,[149][150][151][152] Recent preclinical studies show that Treg adoptive transfer can both prevent and treat cGVHD in mice with multiorgan system disease. 136,153 Given the failure of Tregs during cGVHD and the challenges of generating sufficient Tregs for adoptive transfer to treat cGVHD patients, restorative approaches to date have focused on low-dose IL-2 administration to expand Tregs in vivo with ;50% of patients showing Treg expansion and some clinical response as long as therapy is continued. 154,155 Recently, the adoptive transfer of Tregs with or without IL-2 and/or rapamycin has begun to be tested in clinical trials in an effort to increase the proportion and depth of patient response.…”

Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease

“…Multiple preclinical studies have highlighted the importance of Tregs in constraining GVHD, and the adoptive transfer of Tregs has been shown to attenuate both the acute (aGVHD) and cGVHD that manifest after SCT (5)(6)(7)(8)(9)(10). While the adoptive transfer of Tregs after SCT has the therapeutic potential to promote tolerance, the low frequency of these cells, the time required to expand them in vitro to relevant numbers, and their instability after transfer represent limitations for the translation of Treg-based immunotherapy into the clinic.…”

Epigenetic Regulation of Dendritic Cell Development and Function

“…For example, DCs derived from engrafted donor HSPCs display aberrant phenotype and function in mice undergoing allogenic hematopoietic stem cell transplantation. 98–101 While cDC2-like cells in the spleen have impaired antigen-presenting function, 98,99 CD103 + cDC1 shows augmented capacity to mediate alloreactive T-cell responses. 102 We have previously discovered that generation of thymic DCs and DLL4 + DCs from engrafted donor HSPCs is impaired in transplant mice with graft-versus-host disease.…”