RNA-binding proteins and control of mRNA metabolism in the regulation of adaptive immunity in humans

Post-transcriptional gene regulation can determine mRNA splicing, stability, translation and sub-cellular localization, thereby potentially impacting all cellular functions. In the immune system, the importance of post-transcriptional control in regulating the differentiation and functions of T lymphocytes is becoming increasingly clear, although many questions remain to be addressed. RNA-binding proteins (RBPs) have been variably involved in immune modulation by regulating target mRNA stability and translation. These include Argonaute proteins, involved in microRNA (miRNA)-mediated recognition of target mRNAs, CCCH zinc finger proteins including tristetraprolin (TTP) or Roquin-1, -2 and the Regnase family proteins (ZC3H12A, B, C, D) (1, 2) interacting with AU-rich elements or stem-loop structures, respectively. Lastly, the most recently described family of YTH domain-containing RBPs was shown to interact with m6A-modified mRNAs. Understanding mechanisms of post-transcriptional regulation of gene expression is particularly important for immune cells, in which the expression of effector molecules such as cytokines must increase rapidly in response to danger signals, but it also must be quickly turned off to avoid excessive inflammation and tissue damage. Indeed, many mRNAs encoding for cytokines and other immune-relevant genes are unstable and/ or kept in a translationally silenced state until needed. However, there are still major gaps in our knowledge regarding the mechanisms of action of RBPs and their functional role in immune cells, especially in humans. Most importantly, the level of cross-interaction, cooperation or redundancy of the different RBPs in regulating the metabolism of specific mRNAs remains almost completely unknown.