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CD6 facilitates adhesion between T cells and antigen-presenting cells through its interaction with CD166\/ALCAM (activated leukocyte cell adhesion molecule), and physically associates with the T cell receptor (TCR) at the center of the immunological synapse. However, its precise role during thymocyte development and peripheral T cell immune responses remains to be defined. Here, we analyze the in vivo consequences of CD6 deficiency. CD6\u2212\/\u2212 thymi showed a reduction in both CD4+ and CD8+ single-positive subsets, and double-positive thymocytes exhibited increased Ca2+ mobilization to TCR cross-linking in vitro. Bone marrow chimera experiments revealed a T cell\u2013autonomous selective disadvantage of CD6\u2212\/\u2212 T cells during development. The analysis of TCR-transgenic mice (OT-I and Marilyn) confirmed that abnormal T cell selection events occur in the absence of CD6. CD6\u2212\/\u2212 mice displayed increased frequencies of antigen-experienced peripheral T cells generated under certain levels of TCR signal strength or co-stimulation, such as effector\/memory (CD4+TEM and CD8+TCM) and regulatory (T reg) T cells. The suppressive activity of CD6\u2212\/\u2212 T reg cells was diminished, and CD6\u2212\/\u2212 mice presented an exacerbated autoimmune response to collagen. Collectively, these data indicate that CD6 modulates the threshold for thymocyte selection and the generation and\/or function of several peripheral T cell subpopulations, including T reg cells.<\/jats:p>","DOI":"10.1084\/jem.20151785","type":"journal-article","created":{"date-parts":[[2016,7,4]],"date-time":"2016-07-04T14:12:22Z","timestamp":1467641542000},"page":"1387-1397","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":85,"title":["CD6 modulates thymocyte selection and peripheral T cell homeostasis"],"prefix":"10.1084","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4923-2083","authenticated-orcid":false,"given":"Marc","family":"Orta-Mascar\u00f3","sequence":"first","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer, 08036 Barcelona, Spain 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