A unifying model for T cell lineage choice

 25 January 2021   Research News

T cells are crucial components of our adaptive immune system, and as a result our health. They are distinguished from other immune cells by the presence of T cell receptors that vary in specificity from cell to cell. These T cell receptors recognise peptide fragments derived from bacteria, viruses or cancer cells.

There are two major lineages of T cells that are distinguished not just by their function, but also by the expression of the co-receptors CD4 or CD8. CD8+ cytotoxic T cells can directly kill infected or cancerous cells, whereas the CD4+ helper T cells secrete cytokines and help B cells produce antibodies. Both lineages arise from bipotential progenitors that express both CD4 and CD8. One of the unsolved mysteries in the field is how these progenitors figure out which of the two co-receptors is appropriate for their particular T cell receptor.

Research published by the Lymphocyte Development group at the MRC LMS uses a single cell approach to unravel the steps that T cell progenitors go through to determine which T cell lineage to choose.

By analysing cells in transit from the bi-potential progenitor stage towards the helper and cytotoxic T lineages, one cell at a time, the team were able to figure out the order of events that lead up to lineage choice, and to figure out how signal strength informs the process.

The team propose a unifying model where signal strength, aided by a sequence of expression of co-receptors, both contribute to the choice between the CD4 or CD8 T cell receptors. This brings together components from two previous models that described this process.

One of the next challenges for the group will be to directly visualise transitions between co-receptor expression states. Specifically, can progenitors that are destined for the CD8-expressing cytotoxic T lineage progress directly from a CD4+ CD8+ double positive state to a CD8-expressing state, or is there an obligatory stage of CD4 only-expressing state that the cells must go through to get there?

Understanding the steps and the decisions that T cells go through in order to mature is not only important for our understanding of our biology, but it could also help to unravel what might be going wrong in autoimmunity and immune deficiency disorders.


‘The order and logic of CD4 CD8 lineage choice and differentiation in mouse thymus’ was published on 4 January in Nature Communications. Read the full article here.