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TSPAN32) Expression in T Cell-Mediated Immune Responses and in Multiple Sclerosis

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TSPAN32) Expression in T Cell-Mediated Immune Responses and in Multiple Sclerosis International Journal of Molecular Sciences Article Modulation of Tetraspanin 32 (TSPAN32) Expression in T Cell-Mediated Immune Responses and in Multiple Sclerosis Salvo Danilo Lombardo 1 , Emanuela Mazzon 2, Maria Sofia Basile 1, Giorgia Campo 1, Federica Corsico 1, Mario Presti 1 , Placido Bramanti 2, Katia Mangano 1 , Maria Cristina Petralia 2, Ferdinando Nicoletti 1,* and Paolo Fagone 1 1 Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy 2 IRCCS Centro Neurolesi Bonino Pulejo, C.da Casazza, 98124 Messina, Italy * Correspondence: [email protected]; Tel.: +39-095-478-1270 Received: 30 July 2019; Accepted: 30 August 2019; Published: 4 September 2019 Abstract: Tetraspanins are a conserved family of proteins involved in a number of biological processes including, cell–cell interactions, fertility, cancer metastasis and immune responses. It has previously been shown that TSPAN32 knockout mice have normal hemopoiesis and B-cell responses, but hyperproliferative T cells. Here, we show that TSPAN32 is expressed at higher levels in the lymphoid lineage as compared to myeloid cells. In vitro activation of T helper cells via anti-CD3/CD28 is associated with a significant downregulation of TSPAN32. Interestingly, engagement of CD3 is sufficient to modulate TSPAN32 expression, and its effect is potentiated by costimulation with anti-CD28, but not anti-CTLA4, -ICOS nor -PD1. Accordingly, we measured the transcriptomic levels of TSPAN32 in polarized T cells under Th1 and Th2 conditions and TSPAN32 resulted significantly reduced as compared with unstimulated cells. On the other hand, in Treg cells, TSPAN32 underwent minor changes upon activation. The in vitro data were finally translated into the context of multiple sclerosis (MS). Encephalitogenic T cells from Myelin Oligodendrocyte Glycoprotein (MOG)-Induced Experimental Autoimmune Encephalomyelitis (EAE) mice showed significantly lower levels of TSPAN32 and increased levels of CD9, CD53, CD82 and CD151. Similarly, in vitro-activated circulating CD4 T cells from MS patients showed lower levels of TSPAN32 as compared with cells from healthy donors. Overall, these data suggest an immunoregulatory role for TSPAN32 in T helper immune response and may represent a target of future immunoregulatory therapies for T cell-mediated autoimmune diseases. Keywords: TSPAN32; tetraspanins; T cell responses; multiple sclerosis 1. Introduction Tetraspanins are evolutionarily conserved cell-membrane proteins involved in a variety of biological functions, from cell adhesion to intercellular communication and signaling. The tetraspanin family counts 33 different members in the human species: some of them are ubiquitously expressed, others are tissue specific [1]. The tetraspanin structure consists of four transmembrane (TM) domains, with TM domains 1 and 2 flanking a small extracellular loop (SEL), and TM 3 and 4 flanking a large extracellular loop (LEL). Typically, the extracellular regions are involved in protein–protein interactions with other membrane proteins and external ligands, such as integrins, while the intracellular domains mediates the activation of signaling pathways. Tetraspanins are clustered in membrane microdomains, known as tetraspanin-enriched microdomains, that regulate the intracellular transmission of external stimuli [2]. Int. J. Mol. Sci. 2019, 20, 4323; doi:10.3390/ijms20184323 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 4323 2 of 13 Int. J. Mol. Sci. 2019, 20, x 2 of 13 Tetraspanins significantly contribute to different processes of the immune system, as shown from their interactionsTetraspanins with significantly leukocyte contribute proteins such to different as integrins processes and immunoreceptors, of the immune system, which as allows shown these proteinsfrom their to modulate interactions immune with responses leukocyte and proteins processes such such as asintegrins antibody and production, immunoreceptors, T cell proliferation, which leukocyteallows these migration proteins and to extravasation. modulate immune Some responses members and of theprocesses superfamily such as (e.g., antibody CD9, production, CD37 and CD81) T havecell beenproliferation, extensively leukocyte studied migration for their and immune-modulatory extravasation. Some rolemembers in the of co-stimulation the superfamily and (e.g., T cell polarizationCD9, CD37 processes and CD81) [2]. have been extensively studied for their immune-modulatory role in the co-stimulationIn light of their and role T cell in regulatingpolarization immune processes responses, [2]. the tetraspanin superfamily can be a potential target forIn light novel of therapeutic their role in approaches. regulating immune Recent studies responses, have the investigated tetraspanin thesuperfamily contribution can ofbe somea potential target for novel therapeutic approaches. Recent studies have investigated the contribution members of the tetraspanin family to autoimmune diseases, in particular to multiple sclerosis (MS), of some members of the tetraspanin family to autoimmune diseases, in particular to multiple showing a possible involvement in its pathogenesis by controlling the transmigration of lymphocytes sclerosis (MS), showing a possible involvement in its pathogenesis by controlling the transmigration and monocytes to the central nervous system (CNS) [3,4]. However, little is known about the of lymphocytes and monocytes to the central nervous system (CNS) [3,4]. However, little is known pathophysiological role of TSPAN32 (a.k.a. Tssc6) in the regulation of immune responses. about the pathophysiological role of TSPAN32 (a.k.a. Tssc6) in the regulation of immune responses. InIn a previousa previous study, study, Tssc6gt Tssc6gt/gt/gt T cells T cells bearing bearing a null a mutationnull mutation of the of Tssc6 the alleleTssc6 showedallele showed enhanced responsesenhanced to responses stimulation to stimulation due to increased due to IL-2 increased production, IL-2 production, suggesting suggesting that Tssc6 that may Tssc6 play may a role play in the negativea role in regulation the negative of peripheralregulation of T-lymphocyte peripheral T-lymphocyte proliferation proliferation [5]. [5]. TheThe present present study study focuses focuses onon thethe characterization of of TSPAN32 TSPAN32 in in T Tcell cell responses responses and and provides provides thethe first first proof proof of of concept concept for for a possiblea possible role role of of TSPAN32 TSPAN32 in in the the immune immune dysregulation dysregulation observed observed inin MS, definingMS, defining this molecule this molecule as a potential as a potential translational translational target target for furtherfor further studies. studies. 2. Results2. Results 2.1.2.1. TSPAN32 TSPAN32 Expression Expression Analysis Analysis inin ImmuneImmune Cells AnalysisAnalysis of of TSPAN32 TSPAN32 expressionexpression levels in in leukocyte leukocyte populations populations revealed revealed that that TSPAN32 TSPAN32 is is expressedexpressed at at higher higher levels levelsin in thethe lymphoidlymphoid lineage as as compared compared with with myeloid myeloid cells. cells. Among Among the the lymphoidlymphoid cells, cells, cytotoxic cytotoxic T T cells cells expressed expressed lower lower levels levels of of TSPAN32 TSPAN32 while while naïvenaïve TT helperhelper cellscells hadhad the highestthe highest expression expression (Figure (Figure1A). During 1A). During T cell T development, cell development, TSPAN32 TSPAN32 expression expression was was acquired acquired inthe laterin the phases later of phases thymocyte of thymocyte development development (i.e., at (i.e., the stageat the ofstage double of double positive positive cells). cells). In particular, In particular, double negativedouble thymocytesnegative thymocytes showed theshowed lowest the expression,lowest expression, while bothwhile double both double positives positives and single and single positive maturepositive thymocytes mature thymocytes showed the showed highest the expression highest expression levels (Figure levels 1(FigureB). 1B). FigureFigure 1. 1.Expression Expression of of TSPAN32TSPAN32 inin murinemurine immune cells. cells. (A (A) Expression) Expression of ofTSPAN32 TSPAN32 in murine in murine immuneimmune lineages lineages was was evaluated evaluated by by interrogating interrogating the the GSE15907 GSE15907 microarraymicroarray dataset. ( (BB)) Modulation Modulation of theof transcriptomic the transcriptomic levels levels of TSPAN32 of TSPAN32 during during T cell development,T cell development, as determined as determined from the from GSE15907 the dataset.GSE15907 Data dataset. are shown Data asare normalized shown as normalized mean SD mean and ± statisticalSD and statistical analysis analysis performed performed using using one-way ± ANOVAone-way followed ANOVA by followed Bonferroni by Bonferroni multiple testmultiple correction. test correction. Int. J. Mol. Sci. 2019, 20, x 3 of 13 2.2. Tetraspanins Expression in T Cell Activation Analysis of TSPAN32 expression levels during T cell activation showed a time-dependent decrease in the levels of TSPAN32 in effector T cells following anti-CD3/CD28 stimulation. In particular, a significant reduction in TSPAN32 levels was observed starting at 5 h post stimulation (Figure 2A). Anti-CD3 stimulation was sufficient to significantly downregulate TSPAN32 (p < 0.05 vs. the control unstimulated cells), and its effect was potentiated by co-stimulation with anti-CD28 (p < 0.001 vs. the control unstimulated
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