What is it about?
Co-receptors are molecules that help key defensive cells of animals (T cells) determine if their main antigen receptor is specialised to detect peptides from intracellular proteins (CD8 active) or extracellular proteins (CD4 active). CD4 is also famous as the main receptor for the HIV virus that causes AIDS. Co-receptors signal through coupling to lymphocyte kinase (Lck) and there is controversy as to whether most co-receptors bind Lck or only a minority. We analysed co-receptors freshly isolated from cells and single molecule fluorescence fluctuations in live cells to determine that the majority of CD4 and CD8 are bound to Lck. A CD4 specific amphipathic helix results in more Lck binding by CD4 in a direct competition.
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Why is it important?
Co-receptor-Lck complexes enable developing T cells to be correctly programmed as helper or killer T cells based on the type of major histocompatibility complex (MHC) protein recognised by their unique T cell antigen receptor (TCR). We have resolved the controversy regarding the efficiency of coupling with clear results by two approaches that the majority of co-receptors are coupled to Lck. This is critical information for T cell engineering to treat cancer.
Perspectives
Recent work from the Singer lab (Nature Immunology 2022;23:731-42.) reversing the expression pattern of CD4 and CD8 during T cell development confirmed that the timing of coreceptor expression is critical for developmental decisions and not the nature of the different co-receptor signals. The results of our reconsideration are consistent with both CD4 and CD8 being able to form efficient signaling complexes. We also discovered that the amphipathic helix in CD4 increases Lck binding by ~2/3rd compared to CD8. This may compensate for the lower affinity of CD4 than CD8 for respective MHC ligands. Beyond this specific application, we herald line scanning fluorescence correlation spectroscopy as an excellent method for in situ analysis of molecular interactions.
Michael Dustin
University of Oxford
Read the Original
This page is a summary of: The kinase occupancy of T cell coreceptors reconsidered, Proceedings of the National Academy of Sciences, December 2022, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2213538119.
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