Interferon-γ Induces Expression of MHC Class II on Intestinal Epithelial Cells and Protects Mice from Colitis

Thelemann, Christoph; Eren, Remzi Onur; Coutaz, Manuel; Brasseit, Jennifer; Bouzourène, Hanifa; Rosa, Muriel; Duval, Alex; Lavanchy, Christine; Mack, Vanessa; Mueller, Christoph; Reith, Walter; Acha‐Orbea, Hans

doi:10.1371/journal.pone.0086844

Cited by 113 publications

(119 citation statements)

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“…It was previously shown in vivo that IFN-γ is the major cytokine driving the expression of MHCII molecules by nonhematopoietic cells [24]. Moreover, by using an adoptive transfer model of colitis in mice in which IFN-γ is selectively absent on donor and/or recipient mice we had shown that IFN-γ is the exclusive cytokine capable of inducing nonhematopoietic MHCII expression in vivo [25]. Here, we provide evidence that during EAM, MHCII molecules are upregulated mainly on endothelial cells of the cardiac microvasculature, whereas other CD45 − cells, most importantly cardiomyocytes, do not express detectable MHCII molecules.…”

Section: Discussionmentioning

confidence: 79%

“…Accordingly, these mice also show a normal distribution of thymic and peripheral CD4 + naïve, effector, memory, and FoxP3 + T-cell subsets [25]. Furthermore, steady-state frequencies of intestinal CD4 + T cells, including FoxP3 + regulatory T cells, are comparable between pIV−/− K14 CIITA Tg and WT mice.…”

Section: Absence Of Nonhematopoietic Mhcii Expression Prevents Eammentioning

confidence: 83%

“…In a model of chronic gut inflammation, we have previously shown that IFN-γ is the main driver of nonhematopoietic MHCII expression by intestinal epithelial cells, and administration of an anti-IFN-γ monoclonal antibody (mAb) reduced inducible nonhematopoietic MHCII expression in vivo [25]. We therefore aimed to examine how systemic neutralization of IFN-γ influences EAM severity in WT mice.…”

Section: Neutralization Of Ifn-γ Reduces Eam Severity In Wt Micementioning

confidence: 99%

“…pI activity is mainly restricted to myeloid cells and pIII is active in lymphoid cells. Here, we take advantage of the fact that in pIV−/− mice IFN-γ-inducible MHCII expression is specifically abrogated in nonhematopoietic cells [24,25]. It was previously shown that positive selection of CD4 + T cells does not occur in pIV−/− mice due to the absence of MHCII on cortical thymic epithelial cells [24].…”

Section: Introductionmentioning

confidence: 99%

“…It was previously shown that positive selection of CD4 + T cells does not occur in pIV−/− mice due to the absence of MHCII on cortical thymic epithelial cells [24]. However, transgenic (Tg) expression of CIITA controlled by the keratin-14 (K14) promoter reestablishes thymic CD4 + T-cell selection: The resulting pIV−/− K14 CIITA Tg mice exhibit normal and functional CD4 + T cells and MHCII expression on professional APCs (which are directed by pI and pIII) but selectively miss inducible nonhematopoietic MHCII expression [12,[24][25][26].Here, we investigated the role of nonhematopoietic MHCII expression in myocarditis using the EAM model. We found that lack of inducible nonhematopoietic MHCII expression in pIV−/− K14 CIITA Tg mice protected from EAM.…”

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

et al. 2015

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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 ...

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Section: Discussionmentioning

confidence: 79%

Section: Absence Of Nonhematopoietic Mhcii Expression Prevents Eammentioning

confidence: 83%

Section: Neutralization Of Ifn-γ Reduces Eam Severity In Wt Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2015

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CD4⁺ Cytotoxic T Lymphocytes in Cancer Immunity and Immunotherapy

Wang

et al. 2022

Advanced Biology

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CD4+ T cells have the ability to differentiate into relatively specialized effector subsets after exposure to innate immune signals. The remarkable plasticity of CD4+ T cells is required to achieve immune responses in different tissues and against various pathogens. Numerous studies have shown that CD4+ T cells can play direct and indispensable roles in protective immunity by killing infected or transformed cells. Although the lineage decision of commitment to the CD4+ or CD8+ cell lineage is once thought to be inflexible, the identification of antigen‐experienced CD4+ T cells with cytotoxic activity suggests the existence of unexpected plasticity for these cells. The recognition of CD4+ cytotoxic T lymphocytes (CTLs) and the mechanisms driving the differentiation of this particular cell subset create opportunities to explore the roles of these effector cells in protective immunity and immune‐related pathology. CD4+ CTLs are proven to play a protective role in antiviral immunity. Here, the latest investigations on the phenotypic and functional features of CD4+ CTLs and their roles in antitumor immunity and immunotherapy are briefly reviewed.

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Amateur antigen‐presenting cells in the tumor microenvironment

Darragh

Karam

2021

Molecular Carcinogenesis

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Presentation of tumor antigens is a critical step in producing a robust antitumor immune response. Classically tumor antigens are thought to be presented to both CD8 and CD4 T cells by professional antigen-presenting cells (pAPCs) like dendritic cells using major histocompatibility complexes (MHC) I and II. But recent evidence suggests that in the tumor microenvironment (TME) cells other than pAPCs are capable of presenting tumor antigens on both MHC I and II. The evidence currently available on tumor antigen presentation by epithelial cells, vascular endothelial cells (VECs), fibroblasts, and cancer cells is reviewed herein. We refer to these cell types in the TME as "amateur" APCs (aAPCs). These aAPCs greatly outnumber pAPCs in the TME and could, potentially, play a significant role in priming an antitumor immune response. This new evidence supports a different perspective on antigen presentation and suggests new approaches that can be taken in designing immunotherapies to increase T cell priming.

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Interferon-γ Induces Expression of MHC Class II on Intestinal Epithelial Cells and Protects Mice from Colitis

Cited by 113 publications

References 45 publications

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

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

CD4⁺ Cytotoxic T Lymphocytes in Cancer Immunity and Immunotherapy

Amateur antigen‐presenting cells in the tumor microenvironment

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Interferon-γ Induces Expression of MHC Class II on Intestinal Epithelial Cells and Protects Mice from Colitis

Cited by 113 publications

References 45 publications

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

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

CD4+ Cytotoxic T Lymphocytes in Cancer Immunity and Immunotherapy

Amateur antigen‐presenting cells in the tumor microenvironment

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CD4⁺ Cytotoxic T Lymphocytes in Cancer Immunity and Immunotherapy