The enigmatic role of the CD4 co-receptor in T-cell activation

The interaction between T-cell receptors (TCRs) and peptide-loaded major histocompatibility complexes (pMHCs) is the first step in initiating an immune response. The sensitivity of this response is heightened by the co-receptor CD4 on helper T cells. However, while CD4 is crucial for the T cells proper function, it is not known how CD4 achieves this sensitization.

This is particularly puzzling since the CD4-pMHC interaction on its own is very weak.

It has been hypothesized that CD4 could stabilize the TCR-pMHC interaction, or that it might help to recruit TCR-activating molecules to the TCR.

To understand this, it is essential to know the binding kinetics of the ternary TCR-pMHC-CD4 complex under biologically relevant conditions.

My group has made several key discoveries which allow for extremely weak protein-protein interactions in contacting cells to be measured.

We will in this project build on these breakthroughs and characterize the binding kinetics between pMHC on single cells and TCR and CD4 in model cell membranes.

The importance of the binding parameters on T-cell activation will finally be verified using a novel DNA-based platform that allows for both the distance between, and the binding parameters of, CD4 and TCR to be controlled and varied.

In addition of shedding light on the role of the enigmatic CD4 this can open for designing more efficient immunotherapeutic drugs by incorporating the effect of CD4 in their function.