Post-transcriptional Regulation of IL-21 in Human T Cells

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Project Summary/Abstract: Autoimmune diseases affect over 23 million Americans and impose a huge burden of disease. Many autoimmune diseases are characterized by pathologic T cell-B cell interactions and production of autoantibodies. The T cell populations that help B cells in autoimmune diseases vary in phenotype and include T follicular helper (Tfh) cells, which reside in follicles of secondary lymphoid organs, as well as T peripheral helper (Tph) cells, which are B cell-helper T cells that migrate to inflamed peripheral tissues such as the rheumatoid joint. Both Tfh cells and Tph cells make the cytokine IL-21, a cytokine essential for B cell differentiation into plasmablasts. In addition, both Tfh cells and Tph cells make CXCL13, a potent B cell chemoattractant. While Tph and Tfh cells can make both IL-21 and CXCL13, these two factors show marked differences in regulation: they are induced by different polarizing cytokines, regulated by different transcription factors, and enacted with different kinetics, such that T cells appear to rarely make both factors simultaneously. We hypothesize that the discordant expression of IL-21 and CXCL13 in controlled by a long noncoding RNA IL21AS1, which is highly expressed in T cells that make abundant CXCL13. In this project, we evaluate the hypothesis that IL21AS1 functions as an endogenous siRNA that inhibits IL-21 expression as T cells transition from initial IL-21 production to later CXCL13 production. We will test the effect of IL21AS1 on IL-21 expression in primary human T cells using knockdown and overexpression experiments. We will evaluate the cellular localization of IL21AS1 and its potential processing into endogenous siRNA. We will interrogate how the expression of IL21AS1 changes under conditions that induce either IL-21 or CXCL13 production by T cells. We expect that this project will reveal a novel mechanism regulating the expression of IL-21 in human T cells and the temporal switch in effector functions in these cells. Understanding the molecular control of these key T cell functions may allow new strategies to interfere with Tph and Tfh cell function therapeutically.