PROJECT SUMMARY
Basic research has fueled a revolution in how complex diseases are treated. As our understanding of T cell
activation improves, so will our ability to leverage the latest findings for translational purposes. For example,
synthetic receptors could be used to redirect T cell specificity and functions to treat numerous diseases if they
are able to integrate with a T cell’s intracellular signaling machinery in a way that mimics the native 5-module
receptor complexes that naturally drive T cell responses to peptide antigens presented by MHC molecules
[receptor module = the T cell receptor (TCR); signaling modules = CD3γε, CD3δε, CD3ζζ; coreceptor module =
CD4/CD8]. We have therefore advocated for biomimetic engineering of synthetic receptors. However, our
basic and translational work in this space, along with the basic research from other labs, have taught us that
doing so requires a better understanding of coreceptor function. At present, controversy surrounds how the
TCR-CD3 complex and CD4 work together on the outside of a CD4+ T cells to relay pMHCII-specific
information across the cell membrane. And, on the inside of CD4+ T cells, the dominant paradigm that is
thought to describe pMHCII-specific signal initiation is not supported by recent results of experiments that were
designed to directly test this model. The current proposal will therefore interrogate the molecular mechanisms,
both outside and inside of CD4+ T cells, by which CD4 contributes to pMHCII-specific responses. We will
leverage advances in computational analysis of protein evolution, and co-evolution, to guide structure-function
analysis of the putative docking site for CD4 and TCR-CD3-pMHCII units. We will also work to purify TCR-
CD3-pMHCII-CD4 assemblies for structural characterization. Finally, we will investigate the molecular
mechanisms by which motifs in CD4’s transmembrane, cytoplasmic juxtamembrane, and intracellular regions
work to help initiate and regulate pMHCII-specific responses. Our results will inform our basic understanding of
CD4+ T cell activation, and therefore guide biomimetic engineering of synthetic receptors for therapeutic
purposes.
