Regulation of T Follicular Helper Cell Differentiation by MicroRNAs Changchun Xiao, The Scripps Research Institute Project Summary T cell help is essential for humoral immune responses. A distinct CD4+ effector T cell subset, T follicular helper cells (TFH), provides this help to B cells. TFH cell differentiation and function are essential for generation of high-affinity antibodies and control of chronic virus infection, while TFH cell expansion has been observed in a subset of autoimmune disease patients and several mouse models of autoimmunity, and was shown to play a causative role in disease pathogenesis in some models. Therefore, elucidating the cellular and molecular mechanisms underlying TFH cell differentiation and function is of critical importance for the design of better vaccines and therapies aimed to boost antibody production in infectious settings and mute antibody production in autoimmunity. In preliminary studies we have found that mutant mice with T cell-specific deletion of the miR-17~92 family, which consists of three miRNA clusters that encode thirteen distinct miRNAs, exhibited severely compromised TFH differentiation, germinal center formation, antibody production, and failed to control chronic virus infection. Conversely, T cell-specific miR-17~92 transgenic mice spontaneously accumulated TFH cells and developed fatal immunopathology. In this proposal, we will: 1) Dissect the functions of individual miR-17~92 miRNAs in TFH differentiation; 2) Investigate the molecular and cellular pathways through which the miR-17~92 family miRNAs control TFH differentiation; 3) Investigate the roles of additional miRNAs in TFH differentiation and function. We have performed small RNA deep sequencing analysis of TFH cells sorted from immunized mice and identified four miRNA genes highly expressed in TFH cells. We have obtained knockout mice for all these miRNA genes and will use them to study TFH differentiation and function.
Regulation of T Follicular Helper Cell Differentiation by MicroRNAs Changchun Xiao, The Scripps Research Institute Relevance The proposed study will shed light on the ways by which miRNAs control antibody responses. Once the cellular and molecular mechanisms underlying miRNA control of TFH cell differentiation and function have been elucidated, miRNAs themselves and their downstream pathways can become valuable targets for the development of therapeutic regimens to treat autoimmune diseases, boost immune responses in infectious settings, and facilitate the design of better vaccines.
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