Modulation of the B Cell Response
Previous and current research
The fate of developing and mature B cells is determined by antigen binding to
the antigen receptor (BCR) on the B cell surface. At the immature stage, encounter
with high-affinity antigen leads to cell death (a way of preventing the production
of autoreactive cells). In contrast, at the mature B cell stage, the immune
system specifically selects for B cells that recognise the antigen with high
affinity, as production of high affinity antibodies is essential for protective
immunity to viruses and other foreign antigens.
We have been interested for several years in understanding
how B cell fate is determined by antigen – both in regard to the affinity
of the antigen and the way in which it is encountered. No other receptor system
needs to give a graded (and qualitatively modulated) response to ligand that
is dependent on ligand affinity over such a wide range. We have developed a
system which allows us to monitor the affinity dependence of a B cell response. Taking advantage of this system
we have shown that the ability of a B cell to respond to soluble monomeric antigen
is restricted to a range of affinities. This functional range of B cell activation
is also dependent on the form in which antigen is seen by a B cell: either soluble,
complexed with immunoglobulin, or tethered on a cell surface.
We have also extensively used imaging techniques to explore
the cellular and molecular mechanisms leading to the activation of B cells upon
membrane antigen recognition. We observed that when a B cell interacts with
membrane antigens its surface gets dramatically reorganised forming a synapse.
The BCR molecules accumulate at the centre of this synapse, where they are segregated
from coreceptor molecules such as CD45 and CD22 (known to down-regulate BCR
function). This phenomenon is accompanied by a corresponding compartmentalisation
of cytoplasmic effectors in the B cell and leads to very efficient B cell activation.
Future projects
We will use our experimental model together with the latest imaging techniques
to understand the cellular and molecular mechanisms leading to B cell activation.
We will explore how the kinetics of synapse formation and receptor compartmentalisation
will be affected by the density, affinity and the context in which antigen is
seen. We will also focus our attention on the cellular mechanisms behind the
different compartmentalisation of the receptor. This work in combination with
in vivo studies will provide a better understanding how the fate of a
B cell is determined and how it can be regulated.
Goal
We want to understand the cellular and molecular mechanisms by which B cell
activation and fate are controlled.
