Regulation of selection and autoimmunity by miR-181 family miRNAs (123.36)

Abstract

Abstract T cell sensitivity to antigens is regulated during development to ensure proper immunity and tolerance. We previously showed that miR-181a regulates the strength and threshold of T cell receptor signaling by targeting negative feedback molecules. Here we used miR-181 knockout mice to examine the role of miR-181 miRNAs in selection and T cell reactivity to antigens. We found that loss of mir-181ab1 caused an increase in the percent of positively selected CD8 single-positive (SP) cells in the thymi of female HY TCR transgenic mice. However, loss of miR-181 had no effect on the deletion CD8 SP cells in the thymi of male HY mice. Moreover, we showed that loss of mir-181ab1 resulted in two-fold more self-reactive T cells in the periphery after immunization with a self-peptide derived from myelin oligodendrocyte glycoprotein (MOG). Paradoxically, knockout mice exhibited a delayed disease onset in a MOG-dependent mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). In particular, the central nervous systems of knockout mice during disease had similar percentages of MOG-specific T cells, but an underrepresentation of TH17 and T H1-polarized CD4 T cells compared to the periphery. These findings demonstrate that mir-181ab1 also plays a role in modulating the differentiation and function of self-reactive T cells. Together, data from our study illustrate the diverse roles of mir-181ab1 in selection and autoimmunity.