When new disease-fighting immune cells called T cells and B
cells are generated, they are given unique receptors on their
surfaces. These receptors are made randomly and can each recognise
and bind to a different antigen, or foreign substance, enabling our
body to fight a huge range of diseases. When we encounter an
antigen, our immune system makes more of the right cell to fight
off the threat by cloning, in large numbers, the cell with the
relevant receptor.
Now, scientists at the Francis Crick Institute have discovered
how diversity is maintained in the repertoire of T cells antigen
receptors, despite this so-called 'clonal selection' during the
immune response.
George Kassiotis of the Crick (currently based at Mill Hill
Laboratories) explained: "Our T and B cells are each equipped with
a unique antigen receptor. This repertoire of receptors allows us
to recognise virtually any new antigen that enters our bodies
during infection or is generated by mutation in cancer, to initiate
immunity.
"Helper CD4 T cells earned their name because they help the
clonal selection and diversification of B cells, the immune cells
which produce antibodies in response to a threat. But who helps the
helpers is less well understood."
The work was carried out in a mouse model for infection with a
virus that causes leukaemia. The scientists analysed changes in the
repertoire of virus-specific T cell receptors over the course of
infection. This allowed them to identify successive waves of
cloning of T cells with particular receptors. The results were
confirmed in mice genetically modified to have only certain T cell
receptors.
Dr Kassiotis said: "In addition to recognising and reacting to
foreign antigens, all T cell receptors react weakly with our own
tissues. This low-level self-reactivity ensures that a
randomly-generated T cell receptor is functional. There were two
surprises for us: Firstly, the first T cells to respond are better
at recognising self-antigens, rather than the foreign antigen
itself.
Secondly, subsequent waves of T cells require the participation
of B cells. Thus, B cells are not only helped by CD4 T cells, they
reciprocally help and diversify the T cell response."
"Finding out which properties of the T cell receptor determine
the magnitude and duration of the T cell immune response is an area
of intense investigation due to its biomedical implications. For
example, this knowledge is essential in the selection of
appropriate T cell receptors to treat cancer or infection,
particularly in chronic disease where long-term treatment is
required."
The paper, Stepwise B-cell-dependent expansion of T helper
clonotypes diversifies the T-cell response, is published inNature Communications.