Control of NKT cell maturation and homeostasis

Natural Killer T (NKT) cells are activated during bacterial, viral and parasitic infections, secreting prodigious amounts of panoply of cytokines that affect other immune cells as well as directly contributing to pathogen clearance. Both beneficial and harmful roles for NKT cells have been described for a number of autoimmune and chronic inflammatory diseases, and NKT cells have been implicated in recognition of malignancies. Thus, an improved understanding of this versatile cell type will provide insights into their paradoxical roles in host protection, immunopathology, and autoimmunity. While numerous transcription factors have been implicated in NKT cell maturation, it is not understood how they cooperate to promote specification to the NKT cell lineage and support the unique functional characteristics of this important cell type. Professor AW Goldrath recently discovered that E protein transcription factors and their inhibitors, the Id proteins, control several key aspects of NKT cell development and homeostasis. This proposal seeks to expand our understanding of important biological questions raised by the initial observations. First, we will establish the relative roles of Id2 versus Id3 and HEB versus E2A in the control of NKT cell maturation, survival, and function. Second, our studies will explore the molecular basis for cooperative and distinct functions of E protein family members, a topic that is of broad interest in hematopoiesis and lymphoid development as well as NKT cell maturation and function. Specifically we propose the following aims: Aim 1: Establish the role of E protein transcription factors in NKT cell development, effector function and homeostasis. Aim 2: Define how Id proteins regulate maturation, homeostasis, and function of NKT cells. These studies will allow us to define the specific mechanisms by which E/Id proteins function in the context of NKT cell development, activation, and homeostasis and to gain an understanding of their role in establishing the transcriptional network driving the NKT cell fate.

Natural killer T ( NKT) cells are highly specialized cells of the immune system that recognize lipid constituents of bacteria and activate the immune system by means of special chemical messengers within a few hours. Since this early warning system also influences the type of immune response , it is not surprising that changes in NKT cell number or function are associated with excessive (septicemia) or misguided (autoimmune diseases) immune responses. What factors are responsible for the control of NKT cell maturation and function is elusive. In my work at the University of California, San Diego I was able to identify proteins in NKT cells that control both maturation and function of these important cells.E - and Id-proteins are regulators of the cellular genomic program. We were able to show that different Id-proteins are present in NKT cells of different function and maturation stages. Mice lacking one or more of these proteins had significant changes in both NKT cell numbers and function. Shifting the balance between E- and Id- proteins resulted in either acceleration or stop of NKT cell maturation. Thus, we were able to increase or decrease the total number of NKT cells. Furthermore, we could show that, Id proteins regulated secretion of chemical messengers by NKT cells; thereby influencing the immune response. Based on our results, it would be possible to develop future drugs that inhibit E or Id proteins, thus enabling new approaches in the treatment of sepsis or rheumatic diseases.