Maintaining diverse antigen receptors on infection-fighting T cells

Image: T cells, painted in different colours to indicate the diversity (and selection of the blue one). Credit: NIAID

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.