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Received Dec 1, 2017; Accepted Feb 8, 2018
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1. Introduction
Allergic asthma is a complex inflammatory disease, characterized by a Th2-skewed immune response [1]. Upon exposure of asthmatics to an allergen, antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, present peptides derived from the allergen to naïve CD4 T lymphocytes in the context of MHC class II molecules (MHC II), followed by costimulatory signals delivered by CD86. Both MHC II and CD86 are targeted for ubiquitination by March1, a member of the membrane-associated RING-CH (March) family of E3 ubiquitin ligases [2, 3]. Ubiquitinated MHC II and CD86 are targeted for lysosomal degradation, thereby inhibiting these molecules from recycling on cell surface in the resting state [2, 4]. Upon activation, March1 expression in DCs and B lymphocytes is inhibited to increase the stability of MHC II on the cell surface and maximize antigen presentation to naïve T cells [5–7]. In line with these observations, IL-10, a potent anti-inflammatory cytokine, stimulates March1 expression and consequently downregulates expression of MHC II in human primary monocytes and mouse bone marrow-derived macrophages [8–10]. Further, March1-mediated MHC II ubiquitination is required for DCs to produce antigen-specific regulatory T cells [11], which in turn impair DC function ability to activate CD4 T cells in an IL-10/March1-dependent manner [12]. These studies suggest that March1 may attenuate allergic reactions in vivo.
Paradoxically, bone marrow-derived conventional DCs (cDCs) from March1-deficient mice presented OVA peptide to naïve CD4 T cells in vitro efficiently, but their ability to activate CD4 T cells was significantly reduced compared to cDCs from March1-sufficient mice. This suppression was attributable to loss of MHC II (and not CD86) ubiquitination [7]. Moreover, Th1/Th17 differentiation of naïve CD4 T cells was inhibited when they were cocultured with March1-deficient cDCs [7]. According to these studies and considering the impact of MHCII/costimulators signals strength in T cell polarization [13], March1 deficiency may lead to impaired immune responses and modulate subsequent asthmatic features of allergy. Whether March1 deficiency attenuates, exacerbates, or modulates allergic lung inflammation in an in vivo model remains elusive. Thus, we assessed...