King's College London

Researchers at King’s College London looked at the development of B cells – the immune cells responsible for making proteins called antibodies that protect the body from infection. B cells are made in the bone marrow, but before they are fully equipped to fight infection, they enter the blood and recirculate between the peripheral bloodstream and other immune sites within our body, where they complete their maturation and are ready to be activated after recognition of specific types of microbes.

The team had previously studied B cells at the point they left the bone marrow. They saw that B cells leaving the bone marrow split into two distinct groups on their journey to becoming mature B cells. They either became B cells that act as the first responders to specific types of bugs, including bacteria that cause lung infection, or B cells with the ability to make long-lasting immune responses against other infectious agents the body has already encountered through previous infections or vaccines.

Which type of B cell they became appeared to be linked to how much of a ‘sensor’ protein they had on their cell surface. This sensor protein, known as IgM, has an important role in recognising foreign invaders in the body.

In the new study, published in Nature Communications, the team looked in greater detail at the fork in the road that B cells encounter during their development.

“Following our initial observations, we wanted to look for proof of this split in B cell development by looking at the DNA itself,” said Professor Jo Spencer, Professor of Experimental Medicine at King’s College London and co-senior author of the paper.

Using B cells isolated from blood samples of healthy adults, they looked specifically at the epigenetics (changes on top of DNA that control which genes are switched on or off, or how much of a particular gene is expressed) of B cells with high and low levels of surface IgM.

The B cells with high levels of IgM had a different epigenetic profile to those with low IgM. These same differences were also observed in B cells produced before birth, isolated from umbilical cord samples – suggesting the fate of the B cells is determined even before encountering a microbe.

These epigenetic features were retained by groups of mature B cells capable of distinct responses to microorganisms, where they were found to be associated with active expression of the genes that had been switched on at earlier stages.

These new insights pave the way for studies to understanding whether the different B cell pathways could be targeted to manipulate the immune response.

“We’re now looking at how these branches of B cell development are impacted in autoimmune diseases where the B cell profiles change, to understand if we can manipulate these developmental branches for health benefit,” added Professor Spencer.

This work was supported by grants from Wellcome and the UKRI Medical Research Council.