miR-21 sustains CD28 signalling and low-affinity T-cell responses at the expense of self-tolerance
DOI: 10.1002/cti2.1321 Objective miR-21 is highly expressed in iNKT and activated T cells, but its T-cell autonomous functions are poorly defined. We sought to investigate the role of miR-21 in the development and functions of T and iNKT cells, representing adaptive and innate-like populations, respectively. Methods We studied mice with a conditional deletion of miR-21 in all mature T lymphocytes. Results Thymic and peripheral T and iNKT compartments were normal in miR-21 KO mice. Upon activation in vitro, miR-21 depletion reduced T-cell survival, TH17 polarization and, remarkably, T- and iNKT-cell ability to respond to a low-affinity antigens, without altering their response to high-affinity ones. Mechanistically, miR-21 sustained CD28-dependent costimulation pathways required to lower the T-cell activation threshold, inhibiting its repressors in a positive feedback circuit, in turn increasing T cell sensitivity to antigenic stimulation and survival. Upon immunization with the low-affinity self-epitope MOG35–55, miR-21 KO mice were indeed less susceptible than WT animals to the induction of EAE, whereas they mounted normal T-cell responses against high-affinity viral epitopes generated upon LCMV infection. Conclusion The induction of T cell responses to weak antigens (signal 1) depends on CD28 costimulation (signal 2). miR-21 sustains CD28 costimulation, decreasing the T-cell 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-antigens by autoreactive immune responses. Thus, miR-21 fine-tunes T-cell response and self/non-self discrimination.