Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

Abstract

Experimental autoimmune myocarditis (EAM) is a CD4 + T-cell-mediated model of human inflammatory dilated cardiomyopathies.Heart-specific CD4 + T-cell activation is dependent on autoantigens presented by MHC class II (MHCII) molecules expressed on professional APCs. In this study, we addressed the role of inflammation-induced MHCII expression by cardiac nonhematopoietic cells on EAM development. EAM was induced in susceptible mice lacking inducible expression of MHCII molecules on all nonhematopoietic cells (pIV−/− K14 class II transactivator (CIITA) transgenic (Tg) mice) by immunization with α-myosin heavy chain peptide in CFA. Lack of inducible nonhematopoietic MHCII expression in pIV−/− K14 CIITA Tg mice conferred EAM resistance. In contrast, cardiac pathology was induced in WT and heterozygous mice, and correlated with elevated cardiac endothelial MHCII expression. Control mice with myocarditis displayed an increase in infiltrating CD4 + T cells and in expression of IFN-γ, which is the major driver of nonhematopoietic MHCII expression. Mechanistically, IFN-γ neutralization in WT mice shortly before disease onset resulted in reduced cardiac MHCII expression and pathology. These findings reveal a previously overlooked contribution of IFN-γ to induce endothelial MHCII expression in the heart and to progress cardiac pathology during myocarditis. Keywords: CD4 + T cells Experimental autoimmune myocarditis (EAM) Endothelial antigen presentation Interferon-γ MHC class IIAdditional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Hans Acha-Orbea e-mail: hans.acha-orbea@unil.ch C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 656-664 Immunomodulation 657 IntroductionInflammatory dilated cardiomyopathy is a common cause of heart failure in young patients and often results from myocarditis in predisposed individuals [1]. CD4 + T-cell-mediated experimental autoimmune myocarditis (EAM) is a model for inflammatory heart disease and is induced in mice either by immunization with α-myosin heavy chain (α-MyHC) derived peptides emulsified in CFA [2][3][4] or by vaccination with α-MyHC-loaded activated dendritic cells (DCs) [5]. Typically, both Th1 and Th17 cells are induced during the course of EAM. It is assumed that both of these subsets mediate myocarditis as mice deficient in either interleukin 17 (IL-17) or interferon γ (IFN-γ) develop cardiac pathology [6,7]. Remarkably, heart-specific autoimmune inflammation has been shown to be a consequence of impaired central tolerance induction to α-MyHC during T-cell development in mice and in humans [8]. CD4 + T-cell-orchestrated immune responses are driven by MHC class II (MHCII) mediated antigen presentation. MHCII is primarily expressed on professional APCs. Cardiac APCs were suggested to present cardiac myosin before the onset of cardiac pathology [9], and DCs, the major APC subset able to initiate primary immune responses, were shown to be critical for ...

IFN-γ versus IL-17: A Battle During Cardiac Autoimmunity Evolution

“…Data obtained in experimental autoimmune cardiomyopathy models using immunization with α-Myhc showed a predominance of CD4 + T-cell response [41,77,78,81]. The transfer of CD4 + T-cells from mouse spleen that produced anti-myosin antibodies and developed cardiomyopathy mimics the disease in severe combined immunodeficiency (SCID) mice.…”

“…In addition to antigen-presenting cells, other cell types of non-hematopoietic lineage can also present antigens to CD4 + T-cells via MHC II under inflammatory stimuli [39]. It has been shown in patients and in rodent models that the MHC II expression by non-hematopoietic cells, in particular endothelial cells, contributes to the development of cardiomyopathy [40,41]. Mice developed lower cardiac commitment when they did not express MHC II in endothelial cells [41].…”

“…It has been shown in patients and in rodent models that the MHC II expression by non-hematopoietic cells, in particular endothelial cells, contributes to the development of cardiomyopathy [40,41]. Mice developed lower cardiac commitment when they did not express MHC II in endothelial cells [41]. Finally, properly activated CD4 + T-cells are able to activate B-lymphocytes to produce and secrete antibodies against cardiac antigens.…”

A genome-wide screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation

“…For CD4 + T cells, the binding of the T cell receptor (TCR) to the peptide-loaded major histocompatibility complex class II (MHCII) on the surface of APCs is necessary for both CD4 + T cell activation and their continued effector function in peripheral tissues (3)(4)(5). Dysregulation of MHCII control leads to a variety of conditions including the development autoimmunity and increased susceptibility to pathogens and cancers (6)(7)(8)(9)(10). While MHCII is constitutively expressed on dendritic cells and B cells, the production of the cytokine IFNg promotes MHCII expression broadly in other cellular populations including macrophages (11)(12)(13)(14).…”

Chemical and genetic control of IFN γ‐induced MHCII expression

“…Expression of MHCII is limited to antigen-presenting immune cells such as dendritic cells and B cells. This is important in a series of pathologies, including the onset of graft-versus-host disease (GVHD) [6,7], transplant rejection [8,9], autoimmune diseases [10], as well as T-cell priming by tumour cells [11,12]. This is important in a series of pathologies, including the onset of graft-versus-host disease (GVHD) [6,7], transplant rejection [8,9], autoimmune diseases [10], as well as T-cell priming by tumour cells [11,12].…”