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The Effects of Interferons on Allogeneic T Cell Response in GVHD: the Multifaced Biology and Epigenetic Regulations

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The Effects of Interferons on Allogeneic T Cell Response in GVHD: the Multifaced Biology and Epigenetic Regulations REVIEW published: 08 July 2021 doi: 10.3389/fimmu.2021.717540 The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations Chenchen Zhao 1,YiZhang 2* and Hong Zheng 1* 1 Penn State Cancer Institute, Penn State University College of Medicine, Hershey, PA, United States, 2 Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, United States Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. This beneficial effect is derived mainly from graft- versus-leukemia (GVL) effects mediated by alloreactive T cells. However, these alloreactive T cells can also induce graft-versus-host disease (GVHD), a life-threatening complication after allo-HSCT. Significant progress has been made in the dissociation of GVL effects Edited by: from GVHD by modulating alloreactive T cell immunity. However, many factors may Jaebok Choi, fl Washington University School of in uence alloreactive T cell responses in the host undergoing allo-HSCT, including the Medicine in St. Louis, United States interaction of alloreactive T cells with both donor and recipient hematopoietic cells and Reviewed by: host non-hematopoietic tissues, cytokines, chemokines and inflammatory mediators. Cameron Scott Bader, Interferons (IFNs), including type I IFNs and IFN-g, primarily produced by monocytes, Stanford University, United States Daniel Peltier, dendritic cells and T cells, play essential roles in regulating alloreactive T cell differentiation University of Michigan, United States and function. Many studies have shown pleiotropic effects of IFNs on allogeneic T cell *Correspondence: responses during GVH reaction. Epigenetic mechanisms, such as DNA methylation and Yi Zhang fi ’ [email protected] histone modi cations, are important to regulate IFNs production and function during Hong Zheng GVHD. In this review, we discuss recent findings from preclinical models and clinical [email protected] studies that characterize T cell responses regulated by IFNs and epigenetic mechanisms, Specialty section: and further discuss pharmacological approaches that modulate epigenetic effects in the This article was submitted to setting of allo-HSCT. Alloimmunity and Transplantation, a section of the journal Keywords: type I interferon, IFN- g, GVHD, epigenetic regulation, alloreactive T cells Frontiers in Immunology Received: 31 May 2021 Accepted: 25 June 2021 INTRODUCTION Published: 08 July 2021 Citation: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides the long-term effective Zhao C, Zhang Y and Zheng H and curative treatment for patients with hematological malignancies. The therapeutic benefit of allo- (2021) The Effects of Interferons HSCT is primarily attributed to the graft-versus-leukemia (GVL) effect, which is mainly mediated on Allogeneic T Cell Response in by infused donor T cells (1). However, these allogeneic T cells can also cause harmful graft-versus- GVHD: The Multifaced Biology – fi and Epigenetic Regulations. host disease (GVHD) (2 4). Acute GVHD is a major risk for non-relapse mortality in the rst 200 Front. Immunol. 12:717540. days after allo-HSCT (5). Therefore, maintaining the beneficial GVL effect while reducing GVHD is doi: 10.3389/fimmu.2021.717540 the holy grail of allo-HSCT. Frontiers in Immunology | www.frontiersin.org 1 July 2021 | Volume 12 | Article 717540 Zhao et al. Interferons Regulate T-Cell-Mediated GVHD Upon stimulation by host antigen-presenting cells (APC), antiviral and antitumor activity by up-regulating MHC-I and infused donor T cells are activated to undergo robust subsequently promoting antigen presentations. proliferation and effector differentiation (2, 6). These APCs IFN-a/b has context-dependent roles in CD4+ Tcell express high levels of antigen-presenting molecule MHC class activation, differentiation and survival (26). IFN-a is associated II and costimulatory molecules (e.g., CD80, CD86), which are with CD4+ T cell activation and contributes to the IFN-g- required to activate allogeneic T cells and promote expansion of mediated Th1 response (27). In contrast, IFN-a/b may activated T cells, respectively. Many cytokines, such as IL-2 and suppress Th2 differentiation of human CD4+ T cells. IL-12, are important for instructing these activated T cells to Importantly, IFN-a regulation of T cell differentiation appears differentiate into effector cells mediating host tissue injury (7, 8). to be context-dependent. Dichotomous T cell polarization Notably, interferons (IFN) have an essential role in regulating T- towards either Th1 or TFH was recently observed depending on cell activities during GVHD (9, 10). Type I (mainly IFN-a/b) the IFN-a exposure at different times (28, 29). In a colon-targeted and type II (IFN-g) are two major IFNs that mediate GVHD murine model, IFN-a signaling prevented donor CD4+ T pathophysiologic changes during infection, cancer and cell proliferation and differentiation, resulting in alleviating colon autoimmune diseases (11–15). IFN-g is primarily derived from tissue damage (30, 31). Regulatory T cells (Tregs) play essential T helper 1 (Th1) CD4+ T cells and cytotoxic CD8+ T cells once roles in controlling immune tolerance after allo-HSCT (32). adaptive immunity develops, whereas IFN-a can be produced by Adoptive transfer of Treg ameliorates GVHD and improves plasmacytoid dendritic cells (pDCs) (16, 17). Both IFN-g and survival in a murine model (33). However, IFN-a/b has shown IFN-a are pivotal regulators of alloreactive T cell responses that some controversial impacts on Tregs. Some studies suggested that mediate GVHD (18–20). However, optimal control of GVHD by overexpression of IFN-a significantly reduced the frequency of modulating IFN signaling remains challenging. IFN signaling is Tregs in the tolerogenic tumor environment (34). Other studies complex and frequently context-dependent: it can lead to distinct suggested that IFN-a stimulation may increase differentiation of effects at different times or stages of a disease course. IFNs CD4+CD25+FOXP3+ Tregs (iTregs) (35)(Figure 1). regulate T cell functions by regulating a group of intracellular IFN-a/b signaling is essential for antigen-driven CD8+ T cell transcription programs. Epigenetic regulations of molecules in responses. First, differentiation of effector CD8+ T cell was the IFN signaling pathway and the interferon-stimulated genes associated with decreased IFNAR but increased IL-12 receptor, (ISG) are crucial for T cell activity (21, 22). This review focuses whereas augmented IFNAR favors the development of central fi + on how IFNs regulate alloreactive T cell responses and what role memory T (TCM) cell (36, 37). In IFNAR de cient mice, CD8 T epigenetic regulation plays in this process. cells lose the ability to become memory T cells during lymphocytic choriomeningitis virus (LCMV) infection (37, 38). Paradoxically, withdrawal of IFN-a monotherapy in clinical chronic myeloid leukemia resulted in elevated frequency of EFFECTS OF IFNs ON T CELL + peripheral CD8 TCM cells (39). Given that many different DIFFERENTIATION AND FUNCTION types of cells express IFNAR, the difference in regulating DURING GVHD memory formation between IFNAR deficiency and IFN-a monotherapy may be attributable to both direct and indirect Type I IFNs mechanisms. Second, the activation of IFN-a/b signaling in T Type I IFNs contain a subgroup of highly related polypeptides cells could benefit cytokine secretion and cytolytic activity. In that have proven essential in regulating innate and adaptive mice, injection of IFN-a incited substantial primary CD8+ T immunity (23). Approximately 12-14 types of IFN-a and one responses through cross-priming by DCs that were independent type of IFN-b,IFN-ϵ,IFN-k, and IFN-w have been identified (24). of CD4+ T-cell help (40, 41). IFN-a/b signaling plays a co- Intriguingly, although type I IFNs are structurally divergent, only stimulatory role in CD8+ T activation and slows the death of one form of heterodimer receptor, IFNAR, has been found. Thus, activated T cells (42, 43). Moreover, direct activation of all type I IFNs activate the same receptor and many subsequent granzyme B transcription through IFN-a/b in effector CD8+ T cell-signaling activities are shared. IFN-a and IFN-b are well cells contributes to tumor suppression as well as autoimmunity defined and are the main subtypes from the immunological (44, 45). Consistent results were found in the context of GVHD perspective. Virtually all cell types reserve the ability to produce that both CD8-dependent GVHD and GVL effects were variable level of IFN-b, whereas pDCs are the main source of enhanced through IFN-a/b signaling (30). In addition, despite IFN-a (23). Host tissue injuries triggered by conditioning IFN-a/b signaling induces transient attrition of bystander naïve regimens, such as preparative irradiation and chemotherapy, T cells in the wake of T-cell response, it can rapidly activate induce damage-associated molecularpatterns(DAMP)and nonspecific bystander memory CD8+ T cells. Activation of foreign pathogen-associated molecular patterns (PAMP). Type I memory T cells contributes to rapid production of IFNs are among the early cytokines whose production is triggered proinflammatory cytokines including IFN-g (Figure 1)(46–48). by the host and donor APCs after the detection of these danger Clinically, recombinant IFN-a has been used alone or in signals by pattern recognition receptors (PRRs), such as
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