Mammalian target of rapamycin complex 1 signalling is essential for germinal centre reaction

Abstract

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that has been shown to be essential for the differentiation and function of various immune cells. Earlier in vitro studies showed that mTOR signalling regulates B-cell biology by supporting their activation and proliferation. However, how mTOR signalling temporally regulates in vivo germinal centre B (GCB) cell development and differentiation into short-lived plasma cells, long-lived plasma cells and memory cells is still not well understood. In this study, we used a combined conditional/inducible knock-out system to investigate the temporal regulation of mTOR complex 1 (mTORC1) in the GCB cell response to acute lymphocytic choriomeningitis virus infection by deleting Raptor, a main component of mTORC1, specifically in B cells in pre- and late GC phase. Early Raptor deficiency strongly inhibited GCB cell proliferation and differentiation and plasma cell differentiation. Nevertheless, late GC Raptor deficiency caused only decreases in the size of memory B cells and long-lived plasma cells through poor maintenance of GCB cells, but it did not change their differentiation. Collectively, our data revealed that mTORC1 signalling supports GCB cell responses at both early and late GC phases during viral infection but does not regulate GCB cell differentiation into memory B cells and plasma cells at the late GC stage.

Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells

“…The development and maintenance of T FH and GC B cells are tightly linked and the treatment with 2DG could affect directly both cell types. Very little is known on GC B cell metabolism, except that, as T FH cells, GC B cells induced upon immunization require intrinsic mTORC1 activation 58 , 59 . In addition, treatment with rapamycin during influenza infection alters affinity maturation of virus-specific antibodies 60 .…”

Increased mTORC1 activation in salivary gland B cells and T cells from patients with Sjögren’s syndrome: mTOR inhibition as a novel therapeutic strategy to halt immunopathology?

“…The mTOR pathway plays an important role in the development and function of B cells, including in germinal centres 3. In addition, mTOR is critical for differentiation of Tfh cells, which are essential for germinal centre reactions 3.…”

“…The mTOR pathway plays an important role in the development and function of B cells, including in germinal centres 3. In addition, mTOR is critical for differentiation of Tfh cells, which are essential for germinal centre reactions 3. Development of germinal centre-like structures in the exocrine glands is associated with an increased risk of developing B cell lymphoma 2.…”

“…The mammalian/mechanistic target of rapamycin (mTOR) pathway is essential for growth, survival and proliferation of T and B cells and integrates multiple signals from the immune microenvironment, including growth factors, nutrients, and T cell receptor (TCR)/B cell receptor (BCR) engagement 3 4. The serine/threonine kinase mTOR is the catalytic subunit of two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), characterised by the incorporation of the proteins Raptor and Rictor, respectively.…”

Early Emergence of Adaptive Mechanisms Sustaining Ig Production: Application to Antibody Therapy

“…Interestingly, BLIMP-1 positively controls the activity of mammalian target of rapamycin (mTORC1) ( 29 ), which is described as a key metabolic factor since it controls proteins, nucleotides and lipids synthesis ( 30 ). mTORC1 has also been well characterized in B cell development ( 31 , 32 ) but its role in ER stress has emerged only in the last decade with a few studies showing its importance for a sustainable Ig production. mTORC1 inhibition in mature murine PCs leads to a decrease in serum IgM and IgG levels and a failure to induce BiP protein expression ( 33 , 34 ).…”