Understanding thymic acquisition of gamma/delta T cell effector function

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Gamma/delta T cells make non-redundant immune responses to infections such as HIV, influenza, tuberculosis and malaria, and have critical roles in immunopathologies such as psoriasis and multiple sclerosis. Moreover, gamma/delta T cells are now considered attractive candidates for immunotherapy strategies against cancer. Indeed, a recent study of 18,000 cancer patients with 39 different malignancies revealed a tumour-associated gamma/delta T cell expression profile as the single biggest positive prognostic immune-related indicator.Gamma/delta T cells administer their tissue-associated effector functions largely through early provision of cytokines and chemokines that influence both the local tissue environment and downstream alpha/beta T cell-mediated adaptive immune responses. Secretion of interferon gamma (IFN-gamma) and interleukin-17A (IL-17A) are central components to this effector function; for example, IFN-gamma is implicated in anti-viral and anti-tumour immune responses, while IL-17A is critical for clearance of fungal infections.Despite being superficially similar (e.g. expressing a T cell receptor) to alpha/beta T cells, gamma/delta T cells are now recognised as having important differences. Unlike alpha/beta T cells that only commit to specific effector functions during an immune response, gamma/delta T cells acquire their effector function (i.e. to produce IFN-gamma or IL-17A) during development in the thymus. The mechanistic processes that drive this thymic commitment to effector fate are still being explored, but undoubtedly represent a key foundation stone for fully understanding gamma/delta T cell biology.Our recent work on gamma/delta T cell development has led to the following hypotheses; that the gamma/delta T cell receptor (TCR) instructs gamma/delta progenitors to adopt specific fates during thymic development; that engagement of discrete signalling pathways downstream of the gamma/delta TCR drives differential commitment to distinct effector fates, and; that adoption of appropriate metabolic programs is crucial for thymic acquisition of gamma/delta T cell fate and subsequent effector function.To test these hypotheses we will combine state-of-the-art techniques in vitro (e.g. thymus organ cultures, single-cell RNA analyses, retroviral gene transduction) with studies in gene-deficient mice in vivo. In major aim-1, we will assess characteristics of the gamma/delta TCR that drive commitment to distinct effector fates (e.g. importance of the TCR highly variable regions, the sub-type of TCR chain used, the timing of TCR expression, and dependence on binding to activating or inhibitory ligands). In major aim-2, we will examine the importance of discrete signalling networks to adoption of distinct effector fates (e.g. those controlled by PI3-kinase, ERK/MAPK or NF-kappa-B), with emphasis on how these interact with transcription factor networks. Finally, in aim-3 we will assess the mechanisms that regulate the differential metabolic programming of developing gamma/delta T cells and how this impacts on subsequent gamma/delta T cell function.The studies detailed in this proposal will significantly advance the field of gamma/delta T cell biology. Gamma/delta T cells are increasingly considered to connect the broadly reactive, rapidly acting innate immune system with the delayed responses of the pathogen-specific adaptive immune system. Thus, understanding how features of adaptive immunity (e.g. TCR expression/signalling) instruct acquisition of innate-like qualities (e.g. rapid secretion of cytokines) will be particularly illuminating. Moreover, understanding gamma/delta T cell development will provide critical insight into gamma/delta T cell function. In turn, this will better inform augmentation of gamma/delta T cell responses in disease, and will better advise how these cells can be utilized in immunotherapeutic approaches, for example in anti-tumour strategies.