{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:36:38Z","timestamp":1768512998696,"version":"3.49.0"},"posted":{"date-parts":[[2024,7,26]]},"group-title":"Immunology","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T00:00:00Z","timestamp":1721952000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  During activation the T cell transmembrane receptor CD6 becomes incorporated into the T cell immunological synapse where it can exert both co-stimulatory and co-inhibitory functions. Given the ability of CD6 to carry out opposing functions, this study sought to determine how CD6 regulates early T cell activation in response to viral infection. Infection of CD6 deficient mice with a neurotropic murine coronavirus resulted in greater activation and expansion of CD4 T cells in the draining lymph nodes. Further analysis demonstrated that there was also preferential differentiation of CD4 T cells into T follicular helper cells, resulting in accelerated germinal center responses and emergence of high affinity virus specific antibodies. Given that CD6 conversely supports CD4 T cell activation in many autoimmune models, we probed potential mechanisms of CD6 mediated suppression of CD4 T cell activation during viral infection. Analysis of CD6 binding proteins revealed that infection induced upregulation of\n                  <jats:italic>Ubash3a,<\/jats:italic>\n                  a negative regulator of T cell receptor signaling, was hindered in CD6 deficient lymph nodes. Consistent with greater T cell activation and reduced UBASH3a activity, the T cell receptor signal strength was intensified in CD6 deficient CD4 T cells. These results reveal a novel immunoregulatory role for CD6 in limiting CD4 T cell activation and deterring CD4 T follicular helper cell differentiation, thereby attenuating antiviral humoral immunity.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    CD6 monoclonal blocking antibodies are being therapeutically administered to inhibit T cell activation in autoimmune disorders. However, the multifaceted nature of CD6 allows for multiple and even opposing functions under different circumstances of T cell activation. We therefore sought to characterize how CD6 regulates T cell activation in the context viral infections using an\n                    <jats:italic>in vivo<\/jats:italic>\n                    murine coronavirus model. In contrast to its role in autoimmunity, but consistent with its function in the presence of superantigens, we found that CD6 deficiency enhances CD4 T cell activation and CD4 T cell help to germinal center dependent antiviral humoral responses. Finally, we provide evidence that CD6 regulates transcription of its intracellular binding partner UBASH3a, which suppresses T cell receptor signaling and consequently T cell activation. These findings highlight the context dependent flexibility of CD6 in regulating\n                    <jats:italic>in vivo<\/jats:italic>\n                    adaptive immune responses, which may be targeted to enhance anti-viral immunity.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.07.26.605237","type":"posted-content","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T19:40:31Z","timestamp":1722022831000},"source":"Crossref","is-referenced-by-count":0,"title":["CD6 Regulates CD4 T Follicular Helper Cell Differentiation and Humoral Immunity During Murine Coronavirus Infection"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6139-2242","authenticated-orcid":false,"given":"Amber","family":"Cardani-Boulton","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1319-402X","authenticated-orcid":false,"given":"Cornelia 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