Fedeli Maya, Kuka Mirela, Finardi Annamaria, Albano Francesca, Viganò Valentina, Iannacone Matteo, Furlan Roberto, Dellabona Paolo, Casorati Giulia
Experimental Immunology Unit Division of Immunology, Transplantation, and Infectious Diseases IRCCS San Raffaele Scientific Institute Milan Italy.
Vita-Salute San Raffaele University Milan Italy.
Clin Transl Immunology. 2021 Sep 21;10(9):e1321. doi: 10.1002/cti2.1321. eCollection 2021.
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.
We studied mice with a conditional deletion of miR-21 in all mature T lymphocytes.
Thymic and peripheral T and iNKT compartments were normal in miR-21 KO mice. Upon activation , miR-21 depletion reduced T-cell survival, T17 polarisation and, remarkably, T- and iNKT cell ability to respond to 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 immunisation with the low-affinity self-epitope MOG, miR-21 KO mice were indeed less susceptible than WT animals to the induction of experimental autoimmune encephalomyelitis, whereas they mounted normal T-cell responses against high-affinity viral epitopes generated upon lymphocytic choriomeningitis virus infection.
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.
miR-21在不变自然杀伤T细胞（iNKT）和活化的T细胞中高表达，但其在T细胞中的自主功能尚不清楚。我们试图研究miR-21在T细胞和iNKT细胞的发育及功能中的作用，这两类细胞分别代表适应性免疫细胞群和固有样免疫细胞群。
我们研究了在所有成熟T淋巴细胞中条件性缺失miR-21的小鼠。
miR-21基因敲除（KO）小鼠的胸腺和外周T细胞及iNKT细胞区室正常。激活后，miR-21缺失降低了T细胞存活率、T17极化，并且显著降低了T细胞和iNKT细胞对低亲和力抗原的应答能力，而不改变它们对高亲和力抗原的应答。机制上，miR-21维持了降低T细胞激活阈值所需的CD28依赖性共刺激途径，在正反馈回路中抑制其抑制因子，进而增加T细胞对抗抗原刺激和存活的敏感性。在用低亲和力自身表位髓鞘少突胶质细胞糖蛋白（MOG）免疫后，miR-21 KO小鼠确实比野生型（WT）动物更不易诱导实验性自身免疫性脑脊髓炎，而它们对淋巴细胞性脉络丛脑膜炎病毒感染后产生的高亲和力病毒表位产生正常的T细胞应答。
T细胞对弱抗原（信号1）的应答诱导依赖于CD28共刺激（信号2）。miR-21维持CD28共刺激，降低T细胞激活阈值并增加其对抗抗原刺激和存活的敏感性，拓宽免疫监视范围。这是以引发自身免疫为代价的，自身免疫是由自身反应性免疫应答识别弱自身抗原导致的。因此，miR-21微调T细胞应答以及自我/非自我识别。
