Differential control of T cell co-stimulation by LFA-1, CD2, and CD28

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The adaptive immune system is our personalised weapon against invading pathogens with T cells playing a central role within it. Upon recognising antigens, presented as peptide-MHC (pMHC) complexes on antigen-presenting cells, viatheir T cell antigen receptors (TCRs), T cells can be activated, leading to the initiation of an adaptive immune response that clears the pathogen. According to the 2-signal hypothesis of T cell activation, the pMHC-antigen interaction isnecessary but not sufficient for activation. Indeed, co-stimulatory receptors, once engaged with their ligand upon antigen presenting cells (APCs), provide an essential second signal that permits activation to proceed. However, despiteextensive molecular studies highlighting their structural and signalling diversity, the distinct roles of individual costimulatory receptors on the functional response of T cells remains unclear. For example, the co-stimulatory receptorsLFA-1, CD2, and CD28 are part of structurally distinct families yet are all known to increase the sensitivity of T cells to antigen, albeit through different molecular mechanisms, with LFA-1 and CD2, but not CD28, classified as adhesionmolecules. This raises the question of whether these co-stimulatory receptors are functionally redundant or whether they have different phenotypes on other T cell responses. Utilising a combined experimental and computationalapproach, we aim to uncover the individual role of each receptor on the functional phenotypes of T cell activation, which has important implications for improving immunotherapy.This project covers the BBSRC Priority Area of 'Systems Approaches to the Biosciences'. The data collected from experiments is used in conjunction with mathematical models to better understand the role of individual accessoryreceptors in T cell activation.