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Semaphorin4a-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner

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Semaphorin4a-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner International Journal of Molecular Sciences Article Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner 1,2, 3,4, 1,2 1,2 Tiago Carvalheiro y , Carlos Rafael-Vidal y, Beatriz Malvar-Fernandez , Ana P. Lopes , Jose M. Pego-Reigosa 3,4, Timothy R. D. J. Radstake 1,2 and Samuel Garcia 1,2,3,4,* 1 Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands; [email protected] (T.C.); [email protected] (B.M.-F.); [email protected] (A.P.L.); [email protected] (T.R.D.J.R.) 2 Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands 3 Rheumatology & Immuno-mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain; [email protected] (C.R.-V.); [email protected] (J.M.P.-R.) 4 Rheumatology Department, University Hospital Complex of Vigo, 36312 Vigo, Spain * Correspondence: [email protected]; Tel.: +34-986-515-463 These authors equally contributed to this work. y Received: 31 August 2020; Accepted: 19 September 2020; Published: 22 September 2020 Abstract: Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4+ T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naïve Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORγt in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4+ T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4+ T cell-mediated diseases. Keywords: semaphorin4A; plexinD1; CD4+ T cell differentiation; T helper cells; systemic sclerosis 1. Introduction T helper (Th) cells are essential regulators of the adaptive immune responses. There are three major subsets of Th cells, which can be identified based on their cytokine production and immune function. Th1 cells are characterized by the secretion of interferon-γ (IFN-γ) and are involved in the host defense against intracellular pathogens; Th2 cells usually secret interleukin (IL)-4, IL-5 and IL-13 and are critical for mediating immune responses against extracellular parasites; finally Th17 cells mainly produce IL-17, IL-21 and IL-22, and are pivotal in the defense against extracellular bacteria and fungi [1–3]. Dysregulation of Th homeostasis has been implicated in several diseases. Int. J. Mol. Sci. 2020, 21, 6965; doi:10.3390/ijms21186965 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 6965 2 of 11 Hyperactivation of Th1 and Th17 cells confers susceptibility to autoimmune diseases and is associated Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 11 with the pathology of multiple sclerosis (MS), inflammatory bowel disease, systemic sclerosis (SSc), psoriasis,bacteria rheumatoid and fungi [1,2,3]. arthritis Dysregulation (RA) and spondiloarthropaties of Th homeostasis has [ 4been–7]. implicated On the other in several hand, diseases. Th2 cells are implicatedHyperactivation in the pathogenesis of Th1 and of Th17 asthmatic cells andconfers allergic susceptibility diseases [to8 ,9autoimmune]. diseases and is Semaphorinassociated with (Sema) the pathology 4A is a transmembraneof multiple sclero glycoproteinsis (MS), inflammatory belonging bowel to the disease, semaphorin systemic family, whichsclerosis is a large (SSc), group psoriasis, of proteins rheumatoid initially arthritis described (RA) and as spondiloarthropaties axonal guidance molecules [4,5,6,7]. On [10 the]. Sema4A other is mainlyhand, produced Th2 cells byare implicated dendritic in cells, the pathogenesis monocytes of and asthmatic macrophages and allergic [11 diseases], although [8,9]. it can be also expressedSemaphorin by activated (Sema) CD4 4A+ T is cells a transmembrane and germinal glyc centeroprotein B cells belonging [12–14 ].to Sema4Athe semaphorin binds family, to different which is a large group of proteins initially described as axonal guidance molecules [10]. Sema4A is receptors expressed on CD4+ T cells, such as PlexinB1, PlexinB2, PlexinD1, Neuropilin-1 (NRP-1), mainly produced by dendritic cells, monocytes and macrophages [11], although it can be also Immunoglobulin-likeexpressed by activated transcript CD4+ T 4cells (ILT)4 and andgerminal Tim-2, center although B cells the[12,13,14]. last has Sema4A been reportedbinds to different in mice and has noreceptors human expressed orthologous on CD4 [12–+ 18T ].cells, Several such studiesas PlexinB1, have PlexinB2, shown thatPlexinD1, Sema4A Neuropilin-1 expression (NRP-1), is elevated in diseasesImmunoglobulin-like in which Th transcript cells play 4 an(ILT)4 essential and Tim-2, role, although including the asthma,last has been RA, reported MS and in SSc mice [11 and–13 ,19]. Furthermore,has no human functional orthologous studies have[12,13,14,15,16,17,18]. demonstrated thatSeveral Sema4A studies is a keyhave moleculeshown that in the Sema4A regulation of naïveexpression CD4+ isT elevated cell diff inerentiation, diseases in althoughwhich Th ce dillsff erentplay an e ffessentialects in mouserole, including and human asthma, CD4 RA,+ MST cells haveand been SSc reported. [11,12,13,19]. In mice, Furthermore, Sema4A isfunctional involved studies in T cell have priming demonstrated and Th1 that skewing, Sema4A both is a processes key + mediatedmolecule by Tim-2in the [regulation14,20]. Besides of naïve that, CD4 Sema4AT cell differentiation, deficiency induces although Th2 different skewing effects and in enhances mouse the + severityand ofhuman allergic CD4 responsesT cells have [21 been–23 ].reported. Finally, In Sema4A mice, Sema4A induced is involved the expression in T cell priming of IL-17 and by Th1 CD4 + T skewing, both processes mediated by Tim-2 [14,20]. Besides that, Sema4A deficiency induces Th2 cells from autoimmune encephalomyelitis mice [11,24]. In human CD4+ T cells, exogenous Sema4A skewing and enhances the severity of allergic responses [21,22,23]. Finally, Sema4A induced the inducesexpression ILT-4 mediated of IL-17 by Th2 CD4 diff+ erentiationT cells from and, autoimmune on the contrary encephalomyelitis to mice studies, mice [11,24]. inhibits In Th1 human skewing. + Moreover,CD4+ T we cells, also exogenous found that Sema4A Sema4A induces secreted ILT-4 mediated by activated Th2 differentiation CD4 T cells and, of SSc on the patients contrary is ableto to inducemice the studies, expression inhibits of Th17 Th1 cytokinesskewing. Moreover, in a PlexinB2, we also PlexinD1 found andthat NRP-1Sema4A dependent secreted by manner activated [12 ,13]. Altogether,CD4+ T cells of these SSc patients data demonstrate is able to induce that the exogenous expression Sema4A of Th17 cytokines is involved in a in PlexinB2, human PlexinD1 naïve Th cell differentiation.and NRP-1 dependent However, manner whether [12,13]. autocrine Sema4A is involved on this process and the functional consequencesAltogether, of its inhibitionthese data demonstrate are still unknown. that exogenous Sema4A is involved in human naïve Th cell differentiation. However, whether autocrine Sema4A is involved on this process and the functional 2. Resultsconsequences of its inhibition are still unknown. 2.1. Sema4A2. Results Is Induced During CD4+ T Cell Differentiation + Although2.1. Sema4A previous is Induced reports During CD4 have+ T shown Cell Differentiation that Sema4A is not expressed in naïve CD4 T and + only induced after CD4 T cells activation [12,13], its expression during Th cell di+ fferentiation is Although previous reports have shown that+ Sema4A is not expressed in naïve CD4 T and only still unknown.induced after Indeed, CD4+ unstimulated T cells activation naïve [12,13], CD4 itsT cellsexpression did not during express Th SEMA4A. cell differentiation However, is upon still Th1, Th2 andunknown. Th17 diIndeed,fferentiation unstimulated SEMA4A naïve expression CD4+ T cells is did upregulated not express at SEMA4A. day 3, although However, di uponfferences Th1, were only significantTh2 and Th17 in differentiation the Th2 subset. SEMA4A Despite expression the lower is geneupregulated expression at day levels 3, although compared differences to day were 3, at day 7 weonly still observedsignificant an in upregulationthe Th2 subset. of Despite SEMA4A the (Figurelower gene1A). expression In addition, levels we alsocompared determined to day the3, at e ffect of Thday diff
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