{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:23:27Z","timestamp":1789863807556,"version":"4.0.1"},"reference-count":42,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2019,9,4]],"date-time":"2019-09-04T00:00:00Z","timestamp":1567555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"IRCCS \u2018Centro Neurolesi \u2018Bonino Pulejo\u2019","award":["current research funds 2019"],"award-info":[{"award-number":["current research funds 2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tetraspanins are a conserved family of proteins involved in a number of biological processes including, cell\u2013cell 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.<\/jats:p>","DOI":"10.3390\/ijms20184323","type":"journal-article","created":{"date-parts":[[2019,9,4]],"date-time":"2019-09-04T08:28:13Z","timestamp":1567585693000},"page":"4323","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Modulation of Tetraspanin 32 (TSPAN32) Expression in T Cell-Mediated Immune Responses and in Multiple Sclerosis"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6723-7019","authenticated-orcid":false,"given":"Salvo Danilo","family":"Lombardo","sequence":"first","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Mazzon","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi Bonino Pulejo, C.da Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4811-4694","authenticated-orcid":false,"given":"Maria Sofia","family":"Basile","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Campo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Corsico","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5984-1793","authenticated-orcid":false,"given":"Mario","family":"Presti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Placido","family":"Bramanti","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi Bonino Pulejo, C.da Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5920-4620","authenticated-orcid":false,"given":"Katia","family":"Mangano","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"Petralia","sequence":"additional","affiliation":[{"name":"IRCCS Centro Neurolesi Bonino Pulejo, C.da Casazza, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4570-8462","authenticated-orcid":false,"given":"Ferdinando","family":"Nicoletti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6694-1992","authenticated-orcid":false,"given":"Paolo","family":"Fagone","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1080\/19336918.2015.1005465","article-title":"Tetraspanins in Cell Migration","volume":"9","author":"Jiang","year":"2015","journal-title":"Cell Adh. Migr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/nri1548","article-title":"The tetraspanin web modulates immune-signalling complexes","volume":"5","author":"Levy","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.nbd.2008.05.018","article-title":"Targeting the tetraspanin CD81 blocks monocyte transmigration and ameliorates EAE","volume":"31","author":"Dijkstra","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Reyes, R., Carde\u00f1es, B., Machado-Pineda, Y., and Caba\u00f1as, C. (2018). Tetraspanin CD9: A Key Regulator of Cell Adhesion in the Immune System. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00863"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5006","DOI":"10.1128\/MCB.22.14.5006-5018.2002","article-title":"The absence of Tssc6, a member of the tetraspanin superfamily, does not affect lymphoid development but enhances in vitro T cell proliferative responses","volume":"22","author":"Tarrant","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Saiz, M.L., Rocha-Perugini, V., and S\u00e1nchez-Madrid, F. (2018). Tetraspanins as Organizers of Antigen-Presenting Cell Function. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01074"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1073\/pnas.0609665104","article-title":"The tetraspanin CD9 mediates lateral association of MHC class II molecules on the dendritic cell surface","volume":"104","author":"Unternaehrer","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6691","DOI":"10.4049\/jimmunol.169.12.6691","article-title":"Cutting edge: Dynamic redistribution of tetraspanin CD81 at the central zone of the immune synapse in both T lymphocytes and APC","volume":"169","author":"Mittelbrunn","year":"2002","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/eji.200838798","article-title":"Tetraspanins CD37 and CD151 differentially regulate Ag presentation and T cell co-stimulation by DC","volume":"39","author":"Sheng","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3158","DOI":"10.4049\/jimmunol.0902867","article-title":"A Complementary Role for the Tetraspanins CD37 and Tssc6 in Cellular Immunity","volume":"185","author":"Gartlan","year":"2010","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Gustafsson, M., Edstr\u00f6m, M., Gawel, D., Nestor, C.E., Wang, H., Zhang, H., Barren\u00e4s, F., Tojo, J., Kockum, I., and Olsson, T. (2014). Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment. Genome Med., 6.","DOI":"10.1186\/gm534"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Falzone, L., Lupo, G., La Rosa, G.R.M., Crimi, S., Anfuso, C.D., Salemi, R., Rapisarda, E., Libra, M., and Candido, S. (2019). Identification of Novel MicroRNAs and Their Diagnostic and Prognostic Significance in Oral Cancer. Cancers, 11.","DOI":"10.3390\/cancers11050610"},{"key":"ref_13","first-page":"911","article-title":"The analysis of miRNA expression profiling datasets reveals inverse microRNA patterns in glioblastoma and Alzheimer\u2019s disease","volume":"42","author":"Candido","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mammana, S., Fagone, P., Cavalli, E., Basile, M.S., Petralia, M.C., Nicoletti, F., Bramanti, P., and Mazzon, E. (2018). The Role of Macrophages in Neuroinflammatory and Neurodegenerative Pathways of Alzheimer\u2019s Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis: Pathogenetic Cellular Effectors and Potential Therapeutic Targets. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030831"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Fagone, P., Mazzon, E., Cavalli, E., Bramanti, A., Petralia, M.C., Mangano, K., Al-Abed, Y., Bramati, P., and Nicoletti, F. (2018). Contribution of the macrophage migration inhibitory factor superfamily of cytokines in the pathogenesis of preclinical and human multiple sclerosis: In silico and in vivo evidences. J. Neuroimmunol., 322.","DOI":"10.1016\/j.jneuroim.2018.06.009"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Mangano, K., Cavalli, E., Mammana, S., Basile, M.S., Caltabiano, R., Pesce, A., Puleo, S., Atanasov, A.G., Magro, G., and Nicoletti, F. (2018). Involvement of the Nrf2\/HO-1\/CO axis and therapeutic intervention with the CO-releasing molecule CORM-A1, in a murine model of autoimmune hepatitis. J. Cell. Physiol.","DOI":"10.1002\/jcp.26223"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8263","DOI":"10.18632\/oncotarget.23862","article-title":"Preclinical evaluation of the PI3K\/Akt\/mTOR pathway in animal models of multiple sclerosis","volume":"9","author":"Mammana","year":"2018","journal-title":"Oncotarget"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Fagone, P., Muthumani, K., Mangano, K., Magro, G., Meroni, P.L., Kim, J.J., Sardesai, N.Y., Weiner, D.B., and Nicoletti, F. (2014). VGX-1027 modulates genes involved in lipopolysaccharide-induced Toll-like receptor 4 activation and in a murine model of systemic lupus erythematosus. Immunology, 142.","DOI":"10.1111\/imm.12267"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Fagone, P., Mazzon, E., Mammana, S., Di Marco, R., Spinasanta, F., Basile, M.S., Petralia, M.C., Bramanti, P., Nicoletti, F., and Mangano, K. (2019). Identification of CD4+ T cell biomarkers for predicting the response of patients with relapsing-remitting multiple sclerosis to natalizumab treatment. Mol. Med. Rep.","DOI":"10.3892\/mmr.2019.10283"},{"key":"ref_20","first-page":"2881","article-title":"Overexpression of macrophage migration inhibitory factor and functionally-related genes, D-DT, CD74, CD44, CXCR2 and CXCR4, in glioblastoma","volume":"16","author":"Presti","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Fagone, P., Caltabiano, R., Russo, A., Lupo, G., Anfuso, C.D., Basile, M.S., Longo, A., Nicoletti, F., De Pasquale, R., and Libra, M. (2017). Identification of novel chemotherapeutic strategies for metastatic uveal melanoma. Sci. Rep., 7.","DOI":"10.1038\/srep44564"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Basile, M.S., Mazzon, E., Russo, A., Mammana, S., Longo, A., Bonfiglio, V., Fallico, M., Caltabiano, R., Fagone, P., and Nicoletti, F. (2019). Differential modulation and prognostic values of immune-escape genes in uveal melanoma. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210276"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17951","DOI":"10.18632\/oncotarget.24885","article-title":"Pathogenic role for macrophage migration inhibitory factor in glioblastoma and its targeting with specific inhibitors as novel tailored therapeutic approach","volume":"9","author":"Mangano","year":"2018","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.jneuroim.2019.05.006","article-title":"Prevention of clinical and histological signs of MOG-induced experimental allergic encephalomyelitis by prolonged treatment with recombinant human EGF","volume":"332","author":"Nicoletti","year":"2019","journal-title":"J. Neuroimmunol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Petralia, M.C., Mazzon, E., Fagone, P., Russo, A., Longo, A., Avitabile, T., Nicoletti, F., Reibaldi, M., and Basile, M.S. (2019). Characterization of the Pathophysiological Role of CD47 in Uveal Melanoma. Molecules, 24.","DOI":"10.3390\/molecules24132450"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lombardo, S.D., Presti, M., Mangano, K., Petralia, M.C., Basile, M.S., Libra, M., Candido, S., Fagone, P., Mazzon, E., and Nicoletti, F. (2019). Prediction of PD-L1 Expression in Neuroblastoma via Computational Modeling. Brain Sci., 9.","DOI":"10.3390\/brainsci9090221"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.3892\/ol.2015.4031","article-title":"Correlation between the overexpression of Yin Yang 1 and the expression levels of miRNAs in Burkitt\u2019s lymphoma: A computational study","volume":"11","author":"Hafsi","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"747","DOI":"10.3892\/ijmm.2015.2264","article-title":"Identification of novel targets for the diagnosis and treatment of liver fibrosis","volume":"36","author":"Fagone","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Fagone, P., Nunnari, G., Lazzara, F., Longo, A., Cambria, D., Distefano, G., Palumbo, M., Nicoletti, F., Malaguarnera, L., and Di Rosa, M. (2016). Induction of OAS gene family in HIV monocyte infected patients with high and low viral load. Antivir. Res., 131.","DOI":"10.1016\/j.antiviral.2016.04.009"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lombardo, S.D., Mazzon, E., Basile, M.S., Cavalli, E., Bramanti, P., Nania, R., Fagone, P., Nicoletti, F., and Petralia, M.C. (2019). Upregulation of IL-1 Receptor Antagonist in a Mouse Model of Migraine. Brain Sci., 9.","DOI":"10.3390\/brainsci9070172"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.4049\/jimmunol.162.5.2775","article-title":"Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation","volume":"162","author":"Powell","year":"1999","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jaut.2009.06.003","article-title":"Treatment with rapamycin ameliorates clinical and histological signs of protracted relapsing experimental allergic encephalomyelitis in Dark Agouti rats and induces expansion of peripheral CD4+CD25+Foxp3+ regulatory T cells","volume":"33","author":"Donia","year":"2009","journal-title":"J. Autoimmun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.msard.2018.08.009","article-title":"Promising effect of rapamycin on multiple sclerosis","volume":"26","author":"Bagherpour","year":"2018","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0167-5699(98)01320-6","article-title":"Balancing the Th1\/Th2 concept in multiple sclerosis","volume":"19","author":"Laman","year":"1998","journal-title":"Immunol. Today"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zou, F., Wang, X., Han, X., Rothschild, G., Zheng, S.G., Basu, U., and Sun, J. (2018). Expression and Function of Tetraspanins and Their Interacting Partners in B Cells. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01606"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"872","DOI":"10.4049\/jimmunol.1501944","article-title":"Enforced Expression of Hoxa3 Inhibits Classical and Promotes Alternative Activation of Macrophages In Vitro and In Vivo","volume":"197","author":"Burgess","year":"2016","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Vences-Catal\u00e1n, F., and Levy, S. (2018). Immune Targeting of Tetraspanins Involved in Cell Invasion and Metastasis. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01277"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"341","DOI":"10.2165\/11315650-000000000-00000","article-title":"Strategies for Targeting Tetraspanin Proteins","volume":"23","author":"Hassuna","year":"2009","journal-title":"BioDrugs"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/nrd2659","article-title":"Targeting of tetraspanin proteins\u2014Potential benefits and strategies","volume":"7","author":"Hemler","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.4049\/jimmunol.1002695","article-title":"Immunological Genome Project Consortium Transcriptomes of the B and T lineages compared by multiplatform microarray profiling","volume":"186","author":"Painter","year":"2011","journal-title":"J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1007\/s00011-012-0506-y","article-title":"Modulation of heat shock proteins during macrophage differentiation","volume":"61","author":"Fagone","year":"2012","journal-title":"Inflamm. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.1016\/j.celrep.2016.08.036","article-title":"Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis","volume":"16","author":"Hellberg","year":"2016","journal-title":"Cell Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/18\/4323\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:16:34Z","timestamp":1760188594000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/18\/4323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,4]]},"references-count":42,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["ijms20184323"],"URL":"https:\/\/doi.org\/10.3390\/ijms20184323","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,4]]}}}