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
