Type I interferon signaling before hematopoietic stem cell transplantation lowers donor T cell activation via reduced allogenicity of recipient cells

Abstract

Recent studies highlight immunoregulatory functions of type I interferons (IFN-I) during the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that selective activation of IFN-I pathways including RIG-I/MAVS and cGAS/STING prior to allo-HSCT conditioning therapy can ameliorate the course of GVHD. However, direct effects of IFN-Is on immune cells remain ill characterized. We applied RIG-I agonists (3pRNA) to stimulate IFN-I production in murine models of conditioning therapy with total body irradiation (TBI) and GVHD. Using IFN-I receptor-deficient donor T cells and hematopoietic cells, we found that endogenous and RIG-I-induced IFN-Is do not reduce GVHD by acting on these cell types. However, 3pRNA applied before conditioning therapy reduced the ability of CD11c+ recipient cells to stimulate proliferation and interferon gamma expression of allogeneic T cells. Consistently, RIG-I activation before TBI reduced the proliferation of transplanted allogeneic T-cells. The reduced allogenicity of CD11c+ recipient cells was dependent on IFN-I signaling. Notably, this immunosuppressive function of DCs was restricted to a scenario where tissue damage occurs. Our findings uncover a context (damage by TBI) and IFN-I dependent modulation of T cells by DCs and extend the understanding about the cellular targets of IFN-I during allo-HSCT and GVHD.

Interfering With Inflammation: Heterogeneous Effects of Interferons in Graft-Versus-Host Disease of the Gastrointestinal Tract and Inflammatory Bowel Disease

“…In line with that, they could ameliorate disease outcome triggering either the RIG-I/MAVS- or the STING pathway to induce protective type I IFN signaling and maintain intestinal epithelial barrier integrity ( 121 , 123 ). Consistently, several studies could demonstrate, that the administration of type I IFN or type I IFN-inducing agonists was potent in protecting mice from GVHD in a MHC-mismatched model, when given before allo-HCT ( 124 , 125 ). Interestingly, intestinal microbes that produce indole and indole derivatives, mitigate GVHD development, partly by induction of IFN type I-stimulated genes ( 124 ).…”

“…In early clinical studies from the 1990s, pre-transplant exogenous type I IFN administration in humans resulted in increased GVHD occurrence and transplant-related mortality ( 120 , 121 ). In contrast, several experimental studies could demonstrate, that type I IFN signaling was able to positively modulate murine GVHD outcome ( 121 – 125 ). In 2011, Robb and colleagues were amongst the first researchers to investigate the role of type I IFNs in GVHD and GVL.…”

Broad Virus Detection and Variant Discovery in Fecal Samples of Hematopoietic Transplant Recipients Using Targeted Sequence Capture Metagenomics

“…It was shown that activation of the RIG-I/MAVS and cGAS/STING pathways, both innate recognition pathways that induce Interferon type I expression upon sensing of specific viral RNA and DNA sequences, attenuated intestinal GVHD injury ( Fischer et al, 2017 ). Mechanistically, RIG-I activation before HSCT reduced the ability of specific recipient APCs to activate transplanted allogeneic T cells ( Fischer et al, 2019 ). More research is warranted to elucidate the complex correlations between viral presence and the development of GVHD, in which ViroCap could play an important role.…”

Tolerizing Strategies for the Treatment of Autoimmune Diseases: From ex vivo to in vivo Strategies

“…Using a murine GvHD model, TLR7 agonists were found to protect IFNAR1-dependently, involving the tolerogenic action of cDCs and increased Treg responses (22). Furthermore, selective activation of IFN-I pathways prior to hematopoietic stem cell transplantation was shown to be dependent on IFN-I signaling in CD11c + DC, reducing their ability to stimulate allogeneic T cells (23).…”

“…Also, in GvHD, host CD11c + cDCs were shown not to be required for the induction of disease but rather to restrict alloreactive T cell expansion (21). In addition, protection against GvHD was recently revealed to involve the tolerogenic action of both CD8 + cDC1 and CD11b + cDC2 (22,23). In T1D, however, there is preclinical evidence for a predominant tolerogenic role for DCIR2 + cDC2, driving Treg expansion rather than differentiation (2,24).…”