A testing time: understanding more about how the ‘best’ B cells are selected

The production of high quality antibodies that bind a wide range of antigens is essential for the clearance of infectious agents and is the basis for effective vaccination. During the course of an infection the immune cells that produce antibodies, called B cells, go through a process of honing and refinement to maximise the affinity of the antibodies they produce against the antigens of the invading pathogen.

This rigorous process takes place in germinal centres, specialised structures that are found within tissues such as the tonsils, spleen and lymph nodes. Here, antigen specific B cells proliferate, acquire random mutations in the antibody-binding site for antigen, and those B cells carrying antibodies of the highest affinity for antigen are selected to differentiate into antibody secreting cells. The germinal centre provides the training ground for antigen driven selection:  B cells whose mutated antibodies either show no- or low-affinity for the invading antigen enter a self-destruct mode and die, ensuring that only the “gold star”-rated B cells go on to protect us against infection.

Researchers at the Babraham Institute took a detailed look at the role of a gene called microRNA-155 (miR-155) in this process. They were puzzled because deletion of miR-155 in germinal centre B cells disrupts the entire response (see image on the right) while the expression of miR-155 in germinal centre B cells was barely detectable. They started to reconcile these observations when they found that miR-155 is preferentially expressed in a tiny subpopulation of antigen selected B cells.  The researchers then wanted to address why those B cells needed to express miR-155.  They knew that the antigen selected B cells express the proto-oncogene c-Myc and they found that miR-155 promotes the survival of c-Myc positive antigen selected B ells.  These observations explain why deletion of miR-155 impairs the germinal centre response.

Better understanding of the physiology of antibody production may contribute to improving the design of vaccines and stimulation of a more efficient antibody response. The functional link between miR-155 and c-Myc is important because both c-Myc and miR-155 may have oncogenic roles in certain type of lymphomas, such as activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL). These new results may shed some light on the pathogenesis of lymphomas and open up new therapeutic targets.

This research was published in the Journal of Clinical Investigation (December 2015) and supported by MRC funding to Elena Vigorito, a former group leader in the Institute’s Lymphocyte Signalling and Development Programme, and a Marie Curie fellowship to Rinako Nakagawa, and by the BBSRC. Researchers from the Helmholtz Centre for Infection Research, Germany, and the Garvan Institute of Medical Research, Australia, also contributed to this work.
 

Additional resources:

See Rinako and Elena present this work in their Author’s Take video produced for the Journal of Clinical Investigation.

Main image description:

A fluorescent microscopy image showing B and T cells in the germinal centre (naïve B cells – green, T cells – white). The dark and light zones of the germinal centre are shown in blue and red/pink respectively.

Associated researchers (in author order):

Rinako Nakagawa, previous Marie Curie Incoming Fellow (Vigorito group), Lymphocyte Signalling & Development Programme
Rebecca Leyland, MRC funded member of the Vigorito group
Dong Lu, MRC funded postdoc in the Vigorito group
Martin Turner, Head of Lymphocyte Signalling & Development Programme
Giuseppina Arbore, Da Vinci student in the Vigorito group
Elena Vigorito, previous group leader, Lymphocyte Signalling & Development Programme
 

Animal research statement:

As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here used a range of genetically-modified mouse strains to identify the subpopulation of B cells that express miR-155 and to uncover its function. As antigen specific responses are impossible to mimic in the lab experimentally, using an animal model system was essential for these findings.

Please follow the link for further details of our animal research, how we use alternatives whenever possible and our animal welfare practices.
 

Publication reference:

Nakagawa et al. (2015) MicroRNA-155 controls affinity-based selection by protecting c-MYC⁺ B cells from apoptosis. Journal of Clinical Investigation