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We sought to investigate the role of miR\u201021 in the development and functions of T and iNKT cells, representing adaptive and innate\u2010like populations, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We studied mice with a conditional deletion of miR\u201021 in all mature T lymphocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thymic and peripheral T and iNKT compartments were normal in miR\u201021 KO mice. Upon activation <jats:italic>in vitro<\/jats:italic>, miR\u201021 depletion reduced T\u2010cell survival, T<jats:sub>H<\/jats:sub>17 polarisation and, remarkably, T\u2010 and iNKT cell ability to respond to low\u2010affinity antigens, without altering their response to high\u2010affinity ones. Mechanistically, miR\u201021 sustained CD28\u2010dependent costimulation pathways required to lower the T\u2010cell activation threshold, inhibiting its repressors in a positive feedback circuit, in turn increasing T\u2010cell sensitivity to antigenic stimulation and survival. Upon immunisation with the low\u2010affinity self\u2010epitope MOG<jats:sub>35\u201355<\/jats:sub>, miR\u201021 KO mice were indeed less susceptible than WT animals to the induction of experimental autoimmune encephalomyelitis, whereas they mounted normal T\u2010cell responses against high\u2010affinity viral epitopes generated upon lymphocytic choriomeningitis virus infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The induction of T\u2010cell responses to weak antigens (signal 1) depends on CD28 costimulation (signal 2). miR\u201021 sustains CD28 costimulation, decreasing the T\u2010cell activation threshold and increasing their sensitivity to antigenic stimulation and survival, broadening the immune surveillance range. This occurs at the cost of unleashing autoimmunity, resulting from the recognition of weak self\u2010antigens by autoreactive immune responses. Thus, miR\u201021 fine\u2010tunes T\u2010cell response and self\u2010\/non\u2010self\u2010discrimination.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cti2.1321","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T17:44:56Z","timestamp":1632246296000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["miR\u201021 sustains CD28 signalling and low\u2010affinity T\u2010cell responses at the expense of self\u2010tolerance"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9946-3683","authenticated-orcid":false,"given":"Maya","family":"Fedeli","sequence":"first","affiliation":[{"name":"Experimental Immunology Unit Division of Immunology, Transplantation, and Infectious Diseases IRCCS San Raffaele Scientific Institute Milan Italy"},{"name":"Vita\u2010Salute San Raffaele University Milan 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