IMMUNOREG: Memory of Self: Maintenance and memory of immunoregulatory responses

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Regulatory T (Treg) cells are rare immune cells with powerful immunoregulatory functions. Loss of Treg cells results in lethal inflammation, while defects in their function are associated with autoimmunity and allergy. Treg cells also suppress immune responses in cancer. There is intense medical interest in exploiting the powerful functions of Treg cells but efforts to do so have thus far been disappointing - harnessing Treg cells to treat disease remains a major outstanding challenge for the field.To work properly, Treg responses need to be long-lived: Treg cells that develop early in life need to function continuously throughout life to prevent lethal inflammation. Treg populations are maintained as we age despite reduced thymic output of new T cells. Maintenance of Treg responses is also critical to immunoregulatory memory, which limits harmful immune reactions upon repeated exposure to allergens and infection, and to Treg cell therapy. We presently lack a framework for understanding how Treg responses are maintained despite a continuous requirement for their immunoregulatory functions. In many tissues, cell populations are maintained by quiescent stem cells which self-renew while giving rise to shorter-lived progeny. We have recently found that a critical characteristic of stem cells - quiescence - is required for Treg cells to be maintained over long periods of time.Focussing our analyses on inflammatory responses during autoimmune diabetes and neuroinflammation, this research will test the hypothesis that long-lived Treg responses are hierarchically organised, with quiescent self-renewing progenitor cells giving rise to shorter-lived functionally active progeny (Aim 1). We will define molecular mechanisms by which quiescent cells are maintained and how these can be manipulated to improve therapy (Aim 2). By redefining how we think about Treg responses, we will shift the focus from activated Treg cells to their long-lived progenitors whose therapeutic harnessing will benefit patients with inflammatory diseases, transplantation and cancer.