Abstract
CD4+ T cell trafficking is a fundamental property of adaptive immunity. In this study, we uncover a novel role for histone deacetylase 1 (HDAC1) in controlling effector CD4+ T cell migration, thereby providing mechanistic insight into why a T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis (EAE). HDAC1-deficient CD4+ T cells downregulated genes associated with leukocyte extravasation. In vitro, HDAC1-deficient CD4+ T cells displayed aberrant morphology and migration on surfaces coated with integrin LFA-1 ligand ICAM-1 and showed an impaired ability to arrest on and to migrate across a monolayer of primary mouse brain microvascular endothelial cells under physiological flow. Moreover, HDAC1 deficiency reduced homing of CD4+ T cells into the intestinal epithelium and lamina propria preventing weight-loss, crypt damage and intestinal inflammation in adoptive CD4+ T cell transfer colitis. This correlated with reduced expression levels of LFA-1 integrin chains CD11a and CD18 as well as of selectin ligands CD43, CD44 and CD162 on transferred circulating HDAC1-deficient CD4+ T cells. Our data reveal that HDAC1 controls T cell-mediated autoimmunity via the regulation of CD4+ T cell trafficking into the CNS and intestinal tissues.
Highlights
T cell trafficking is a fundamental property of adaptive immunity
To study whether the antigen-specific activation or expansion of CD4+ T cells in vivo is altered in the absence of histone deacetylase 1 (HDAC1), we crossed Hdac1fl/fl and HDAC1cKO mice to 2D2 TCR transgenic mice that express a TCR specific for the myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35-55) [25]
We observed an upregulation of CD25 and CD69 accompanied by a downregulation of CD62L to a similar extent in 2D2-HDAC1cKO and 2D2-WT CD4+ T cells within draining lymph nodes (dLN) (Fig. 1a and b)
Summary
T cell trafficking is a fundamental property of adaptive immunity. The migration of effector CD4+ T cells towards inflamed sites and tissues is key for the coordination of a proper host defense against pathogens. In EAE, activated CD4+ T cells migrate from lymph nodes via the blood and subsequently infiltrate the CNS via several routes that include crossing the endothelial blood-brain barrier (BBB), the epithelial blood-cerebrospinal fluid barrier of the choroid plexus and the sub arachnoid space [2,4]. T cell migration at the BBB (or at other endo thelial barriers) is a multistep process that relies on sequential steps of lymphocyte rolling, arrest, crawling and diapedesis across the endo thelial layer [5]. These steps are regulated via the interaction of cell adhesion molecules and their ligands expressed on activated CD4+ T cells and the inflamed endothelium. The importance of integrins in this process has been exploited for therapeutic purposes, with the integrin α4 chain blocking monoclonal antibody natalizumab approved for MS therapy [17,18]
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