Grant: Operating Grant

Invariant Natural Killer T (iNKT) cells are lymphocytes that respond to lipid antigens presented by a molecule named CD1d. Activated iNKT cells rapidly produce large amounts of various solubles mediators that influence ensuing immune responses. Consistent with this, iNKT cells have protective or deleterious functions during the immune responses associated with cancer, inflammation, autoimmunity and infection. Understanding the mechanisms controlling the activation and functional plasticity of these cells constitutes a major challenge. iNKT cells express particular T cell receptors (TCRs) that are able to recognize a variety of host- (self) as well as microbe-derived lipids presented by CD1d. Self-lipid recognition is important for the development and activation of these cells, although the relevant CD1d-binding self-lipids remain poorly defined. Recent work, including from our group, demonstrated that iNKT TCRs recognize CD1d-lipid complexes in a one-size-fits-all strategy, suggesting that iNKT cells are devoid of antigenic specificity. We further demonstrated that the lipids as well as the TCR composition modulate the affinity between CD1d and iNKT TCRs. Whether the strength of CD1d-lipid-TCR interactions controls iNKT cell responses quantitatively and qualitatively remains an open question. In this proposal, we will address these questions that are a direct extension of our previous work. Our specific goals are to identify CD1d-binding self-lipids and define their regulation of expression in health and disease, as well as their role in iNKT cell development and response. We will also investigate whether the strength of CD1d-lipid-TCR interactions translates into differential biological responses from these cells. The results from the proposed studies will shed light into crucial aspects of iNKT cell biology, and will ultimately help the rational design of novel immunotherapies that target iNKT cells.