Fig. 3. Control of RNA metabolism and function by RBPs in adaptive immune response during autoimmunity and autoinflammation.

RBPs regulate the Th cell differentiation, Treg cell function and B cell activation during development of AIDs via multiple mechanisms. Upper: RBP regulation of Th17 and Tfh cell differentiation. TTP, Regnase-1 and Roquin negatively regulate a set of Th17-related genes such as OX40 via mRNA decay to inhibit Th17 cell differentiation. Regnase-1 and Roquin repress the expression of ICOS and OX40 mRNAs via post-transcriptional regulation to inhibit Tfh cell differentiation. Middle: RBP regulation of Treg cell generation and function. ZFP36L2 decreases Helios expression in Foxp3⁺ Tregs via directly binding to the 3′ UTR of Helios mRNA and destabilizing it, leading to inhibition of iTreg function. Mettl3 mediates m⁶A modification of SOCS mRNA to maintain Treg cell generation and immune tolerance. Roquin upregulates PTEN mRNA expression through antagonizing miR-17–92 binding to PTEN mRNA, and thus suppresses the conversion of Treg to Tfr cells. Bottom: RBP regulation of B cell activation and germinal cell (GC) responses. ZPF36L1 post-transcriptionally limits mRNA levels of transcription factors KLF2 and IRF8 to promote GC response. PTBP1 promotes B cell proliferation and activation in GC via controlling alternative splicing of transcripts of c-Myc target genes such as Pkm and Tyms. lncRNA XIST interacts with TRIM28 to maintain X-inactivation and inhibit X-linked TLR7 gene expression, contributing to restraining of atypical B cell formation. RBPs responsible for each of these steps are shown in red ovals. APC antigen-presenting cells, Th17 IL-17-expressing T cells, Tfh follicular T helper cells, Treg regulatory T cells, iTreg inducible regulatory T cells, Tfr follicular regulatory T cells, TTP tristetraprolin, HuR human antigen R, Arid5a AT-rich interactive domain-containing protein 5a, STAT3 signal transducer and activator of transcription 3, IL-17 interleukin 17, ICOS inducible T cell costimulator, ARE adenine uridine (AU)-rich elements, ZFP36L2 zinc finger protein 36, C3H type-like 2, Ikzf2 IKAROS Family Zinc Finger 2, Mettl3 methyltransferase like 3, SOCS suppressor of cytokine signaling protein, PTEN phosphatase and tensin homolog, ZPF36L1 zinc finger protein 36, C3H type-like 1, IRF8 interferon regulatory factor 8, KLF2 kruppel like factor 2, MZ marginal zone, PTBP1 polypyrimidine tract binding protein 1, Pkm Pyruvate Kinase M, Tyms thymidylate synthetase, TRIM28 tripartite motif containing 28.