Posttranscriptional Gene Regulation of T Follicular Helper Cells by RNA-Binding Proteins and microRNAs

Abstract

T follicular helper (Tfh) cells are critically involved in the establishment of potent antibody responses against infectious pathogens, such as viruses and bacteria, but their dysregulation may also result in aberrant antibody responses that frequently coincide with autoimmune diseases or allergies. The fate and identity of Tfh cells is tightly controlled by gene regulation on the transcriptional and posttranscriptional level. Here, we provide deeper insights into the posttranscriptional mechanisms that regulate Tfh cell differentiation, function, and plasticity through the actions of RNA-binding proteins (RBPs) and small endogenously expressed regulatory RNAs called microRNAs (miRNAs). The Roquin family of RBPs has been shown to dampen spontaneous activation and differentiation of naïve CD4⁺ T cells into Tfh cells, since CD4⁺ T cells with Roquin mutations accumulate as Tfh cells and provide inappropriate B cell help in the production of autoantibodies. Moreover, Regnase-1, an endoribonuclease that regulates a set of targets, which strongly overlaps with that of Roquin, is crucial for the prevention of autoantibody production. Interestingly, both Roquin and Regnase-1 proteins are cleaved and inactivated after TCR stimulation by the paracaspase MALT1. miRNAs are expressed in naïve CD4⁺ T cells and help preventing spontaneous differentiation into effector cells. While most miRNAs are downregulated upon T cell activation, several miRNAs have been shown to regulate the fate of these cells by either promoting (e.g., miR-17-92 and miR-155) or inhibiting (e.g., miR-146a) Tfh cell differentiation. Together, these different aspects highlight a complex and dynamic regulatory network of posttranscriptional gene regulation in Tfh cells that may also be active in other T helper cell populations, including Th1, Th2, Th17, and Treg.

Keywords: Roquin; T follicular helper; T follicular regulatory; miR-146a; miR-155; miR-17–92; microRNAs; regnase-1.

Figure 1

Expression kinetics of major RNA-binding proteins and microRNAs (miRNAs) during T helper cell differentiation. Abbreviations: miRISC, miRNA-induced silencing complex; Ago, Argonaute.

Figure 2

Regulation of T follicular helper cell differentiation and function by major RNA-binding proteins and microRNAs. Abbreviations: TCR, T cell receptor.