The role of B cell - macrophage interactions for adaption to virus escape, memory, and immune tolerance
Lead Research Organisation:
University of Birmingham
Department Name: Immunity and Infection
Abstract
Vaccination induces antibodies that protect us from infection for many years. The same happens during infection. We try to understand how our immune system is able to custom design antibodies that can exactly fit to any random infectious agents we might come into contact with. Antibodies are generated by B cells. The process of B cells adapting to foreign structures on infectious agents happens in lymph nodes and is called B cell affinity maturation. Affinity maturation takes several weeks, which is why vaccination takes weeks to fully protect us.
We recently found that another cell type is important in the process of B cell affinity maturation: phagocytic "eating" cells that can filter and eat infectious agents in the lymph and blood stream. These phagocytes can transfer what they see to B cells, and in this way alert B cells of any new threats emerging. We found that the first thing B cells do after affinity maturation is to interact with phagocytes. It seems that B cells test whether they recognise any of what the phagocytes are carrying. We think this is a very important 1st check to test whether freshly affinity-matured B cells are useful in the long term.
In the current project we plan to better characterise what exactly happens during the interaction of phagocytes and B cells. Which signals can and do phagocytes transfer to B cells? Further, we want to test why this interaction is so important. We think there are several possible explanations: 1) The interaction of phagocytes and B cells can alert B cells that the infectious agent has mutated. This is common in virus infections, e.g. the Covid-19 virus, influenza, or HIV infection. 2) Phagocytes may tell B cells that the infectious agent is still around and instruct them to keep going with affinity maturation, making affinity maturation more efficient. 3) The interaction may alert B cells that they react with structures that are part of the healthy body - self. These self-reactive B cells must be deleted or instructed to affinity-mature away from self-reactivity in order to prevent illness from self-reactive antibody. 4) The interaction may be important to quickly instruct B cells to make protective antibodies.
We plan to test all these possible scenarios. The project should lead to understanding how our immune system deals efficiently with infection and vaccination, how we deal with virus mutants and why during the process we do not become autoimmune to ourselves. Apart from answering these basic questions of biological process, understanding them should help to generate better vaccines or drugs that stimulate our bodies' immune response to infectious agents.
We recently found that another cell type is important in the process of B cell affinity maturation: phagocytic "eating" cells that can filter and eat infectious agents in the lymph and blood stream. These phagocytes can transfer what they see to B cells, and in this way alert B cells of any new threats emerging. We found that the first thing B cells do after affinity maturation is to interact with phagocytes. It seems that B cells test whether they recognise any of what the phagocytes are carrying. We think this is a very important 1st check to test whether freshly affinity-matured B cells are useful in the long term.
In the current project we plan to better characterise what exactly happens during the interaction of phagocytes and B cells. Which signals can and do phagocytes transfer to B cells? Further, we want to test why this interaction is so important. We think there are several possible explanations: 1) The interaction of phagocytes and B cells can alert B cells that the infectious agent has mutated. This is common in virus infections, e.g. the Covid-19 virus, influenza, or HIV infection. 2) Phagocytes may tell B cells that the infectious agent is still around and instruct them to keep going with affinity maturation, making affinity maturation more efficient. 3) The interaction may alert B cells that they react with structures that are part of the healthy body - self. These self-reactive B cells must be deleted or instructed to affinity-mature away from self-reactivity in order to prevent illness from self-reactive antibody. 4) The interaction may be important to quickly instruct B cells to make protective antibodies.
We plan to test all these possible scenarios. The project should lead to understanding how our immune system deals efficiently with infection and vaccination, how we deal with virus mutants and why during the process we do not become autoimmune to ourselves. Apart from answering these basic questions of biological process, understanding them should help to generate better vaccines or drugs that stimulate our bodies' immune response to infectious agents.
Technical Summary
We recently published a new interaction that takes place during B cell affinity maturation in germinal centres (Zhang et al, Nat Comm, 2022, 13, 2460). Memory-like B cells leave germinal centres early on, migrate towards the lymph node subcapsular sinus and there interact with subcapsular sinus macrophages. We have evidence that at this stage antigen-specific interactions happen, antigen is transferred to B cells. While some memory B cells move on into other organs, other B cells after contact with the antigen return to the germinal centre.
We plan to better characterise these interactions by isolating macrophages during these early interactions and testing their gene expression profiles by single cell sequencing. Further, we plan to test the following hypotheses about the role of this interaction:
- Shaping the antibody response to virus escape variants
- Directing the duration of the B cell affinity maturation process
- Sensing self-reactivity of B cells
- Inducing antibody generating plasma cells during the primary immune response
- Finally, test whether macrophage - B cell interactions are involved in rapid recall antibody generation
The project is a collaboration of the team of Yang Zhang and Kai-Michael Toellner, who have worked on germinal centre differentiation for a long time and have found, initially characterised, and published on the new macrophage - B cell interaction and Christopher Mueller, Univ Strasbourg, who is expert in macrophage - stroma interactions, has developed mouse strains that allow specific deletion of macrophage subsets and already collaborates with Yang Zhang on pilot experiments. Co-PI David Bending has developed a new mouse strain (Nur77-Tempo) that is superb in detecting B cell as well as T cell receptor activation using a timer fluorescent reporter gene. DB is interested in T cell and Tfh cell activation during T cell as well as antibody responses.
We plan to better characterise these interactions by isolating macrophages during these early interactions and testing their gene expression profiles by single cell sequencing. Further, we plan to test the following hypotheses about the role of this interaction:
- Shaping the antibody response to virus escape variants
- Directing the duration of the B cell affinity maturation process
- Sensing self-reactivity of B cells
- Inducing antibody generating plasma cells during the primary immune response
- Finally, test whether macrophage - B cell interactions are involved in rapid recall antibody generation
The project is a collaboration of the team of Yang Zhang and Kai-Michael Toellner, who have worked on germinal centre differentiation for a long time and have found, initially characterised, and published on the new macrophage - B cell interaction and Christopher Mueller, Univ Strasbourg, who is expert in macrophage - stroma interactions, has developed mouse strains that allow specific deletion of macrophage subsets and already collaborates with Yang Zhang on pilot experiments. Co-PI David Bending has developed a new mouse strain (Nur77-Tempo) that is superb in detecting B cell as well as T cell receptor activation using a timer fluorescent reporter gene. DB is interested in T cell and Tfh cell activation during T cell as well as antibody responses.
