Post-transcriptional control of T follicular helper cells

Abstract

Antibody production is a key feature of the adaptive immune response. High affinity antibodies neutralise and clear invading pathogens, thereby protecting the host against microbial infections. It is now well-established that T follicular helper (Tfh) cells – a distinct subset of CD4+ T helper cells – are essential in providing cognate help to B cells in the germinal centre (GC) to differentiate into memory and long-lived plasma cells that secrete high affinity antibodies. However, stringent control of Tfh cell numbers is crucial to produce optimally affinity-matured antibody responses that are devoid of self-reactivity. Indeed, excessive number of Tfh cells has been associated with autoimmunity. However, our understanding of the molecular mechanisms controlling Tfh cell differentiation is still incomplete. This thesis focuses on characterising novel post-transcriptional mechanisms that limit Tfh cell numbers. The data presented in this thesis show that RNA-binding proteins, Roquin and its paralogue Roquin-2, cooperate to repress Icos, a key Tfh cell molecule, and limit GC reactions. Mutations in the RING or ROQ domain of Roquin disrupted Icos mRNA regulation, but, unlike the ROQ mutant that still occupied mRNA-regulating stress granules, RING-deficient Roquin failed to localise to stress granules and allowed Roquin-2 to compensate in the repression of ICOS. In addition, the data presented here show that microRNA-146a is highly expressed in human and mouse Tfh cells and its peak expression marks the decline of the Tfh cell response. Loss of miR-146a caused cell-autonomous, spontaneous accumulation of Tfh and GC B cells. Mechanistically, miR-146a acted in both Tfh and GC B cells to control ICOS-ICOSL interactions and limit Tfh and GC B cell numbers. Collectively, Roquin family proteins and miR-146a emerge as novel post-transcriptional brakes on ICOS expression, thus limiting Tfh cell numbers and GC responses.