The role of mucins in controlling T cell antigen sensitivity and discrimination

The family of mucin-like molecules has general biophysical features of extended structure and strong negative charge imparted by extensive sialic acid-terminated glycosylation. Mucins are of biological interest since they modulate intercellular interactions, particularly adhesive interactions between leukocytes, and are stongly implicated in cancer as they reduce lymphocyte immune recognition and clearance. Previous work has highlighted that some mucins such as CD43 act as steric and electrostatic barriers, and reduce adhesion between lymphocytes and antigen presenting cells. Early literature suggests that lymphocytes modulate their mucin content and charge during differentation and activation by post-translational control mechanisms. This will have implications for processes such as antigen presentation and effector functions. The Sattentau lab has demonstrated that mucins have a major role in recognition by phagocytes, particularly in the context of clearance of apoptotic lymphocytes, and we have prepared a number of tools and reagents to investigate the role of mucins in leukocyte interactions. The Dushek lab has long experience in quantitatively analyzing antigen-specific lymphocyte activation and its consequences for function. The project proposed is joint between the two laboratories and is designed to further elucidate how mucins, particularly CD43, modulate T cell activation and effector function and how this might be harnessed to optimise targeting of cancer and pathogen-infected cells. The work will involve cell culture, cell and molecular biology and immunology, and advanced imaging techniques.