Invariant natural killer T (iNKT) cells comprise a sub-lineage of T lymphocytes that express an "invariant" T cell receptor (TCR) with specificity for glycolipid antigens when presented in complex with the MHC class I molecule CD1d. Following TCR engagement, iNKT cells rapidly secrete cytokines and transactivate the anti-tumor functions of dendritic cells (DC), natural killer (NK), T and B cells as well as directly kill tumor cells. Although TCR-CD1d interactions are required for iNKT cell functions, the signaling mechanisms that co-operate with the TCR to promote maximal iNKT cell responses remain poorly understood. Collective studies from our laboratory and others have established that the adaptor protein SAP and its signaling partner, Fyn is critical for iNKT cell development and functions. We investigated the role of ADAP (adhesion and degranulation promoting adaptor protein), a Fyn-binding protein in iNKT cell development and functions. Our studies demonstrate that ADAP is critical for homeostatic maintenance of these cells in peripheral organs. Furthermore, we observe that iNKT cytokine production, and bystander immune cell activation are remarkably reduced in Adap−⁄− mice. These findings are not restricted to the murine system, as ADAP-silenced human iNKT cells also have significantly impaired cytokine release. Importantly, we demonstrate that ADAP is essential for TCR-induced iNKT cell cytotoxicity against leukemia targets in vitro and in vivo. Collectively, our data suggest that ADAP plays a unique linage-specific role in iNKT cells. These studies will have an impact by establishing new paradigms for iNKT cell signaling and offering insights into how iNKT cells can be best activated to enhance host immunity and treat cancer.
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