| iNKT lymphocytes play prominent roles in the control of autoimmunity, tolerance to transplantation, and immune surveillance. Deciphering the mechanisms of iNKT cell development, maturation and activation is critical to understanding the consequences of NKT cell activation upon antigen recognition. Thus, the central goal of this thesis is to define the molecular characteristics of NKT cell antigen recognition and crucial features of their developmental progression and accordingly provide vital insight into their function in vivo . What antigen(s) is recognized by iNKT cells; how iNKT cells recognize antigen; and what molecular factors control iNKT cell development are among the most important unanswered questions in iNKT cell biology. First, using a genetic approach we demonstrate that β-GlcCer is a precursor of the natural antigen recognized by iNKT cells or assists in antigen loading. Second, the biochemistry of iNKT cell antigen recognition was investigated. These studies revealed the avidity and concentration thresholds required for the iNKT cell antigen recognition. Further, we provide evidence that iNKT cell antigen receptor may be structurally different from T cell receptors of conventional CD8 T lymphocytes. Thirdly, and finally, we discovered that NF-κB critically controls iNKT cell development and function. NF-κB exerts its control over iNKT cell development by suppressing Caspase 9-dependent apoptosis. Consequently, this thesis provides novel insights into three questions critical to understanding iNKT cell ontogeny. These insights may aid in the design of new therapeutics for modulation of iNKT cell development and function in health and disease. |
