Grant: Discovery Grants Program - Individual

The nervous and the immune system work towards a common goal ? that is to preserve the homeostasis and to ensure the integrity of the organism in response to perceived threats. Although the existence of intricate crosstalk between the two systems has been long appreciated, our understanding of their interactions at cellular and molecular levels is far from clear. The main goal of the proposed research program is to further our understanding of how the nervous system controls immune responses mediated or regulated by natural killer T (NKT) cells. NKT cells are a rare but remarkably potent subset of lymphocytes with several unusual characteristics. First, they express an invariant T cell receptor that can uniquely recognize glycolipid antigens such as alpha-galactosylceramide (alpha-GalCer). Second, they contain preformed mRNA encoding pro- and anti-inflammatory cytokines typified by interferon (IFN)-gamma and interleukin (IL)-4, respectively. As a result, they secrete enormous quantities of these cytokines very early in the course of an immune response. This results in transactivation of downstream effector cells (e.g., dendritic cells, macrophages, NK cells and conventional T lymphocytes) and dictates the course and nature of immune responses. The responsiveness of NKT cells is greatly influenced by the microenvironment in which these enigmatic cells are activated, which is likely to be shaped by various nervous system mediators. Our understanding of how NKT cells are controlled by such mediators is primitive. The proposed program will explore the effects of various nervous system mediators including but not limited to norepinephrine (NE), neuropeptide Y (NPY) and serotonin (aka. 5-hydroxytryptamine or 5-HT), on NKT cells? regulatory and effector functions. Lymphoid organs are ?hardwired? by sympathetic nerve termini and recent studies suggest that both innate and adaptive immune responses are controlled by the sympathetic nervous system (SNS). However, whether SNS mediators regulate NKT cells that in fact bridge these two arms of immunity is essentially unexplored. In the first cluster of projects defined in this application, we will investigate NKT cell functions in laboratory mice in which the peripheral SNS is rendered ineffective. In addition, we will explore the effects of the SNS mediators NE and NPY on mouse NKT cell responses ranging from alpha-GalCer-triggered proliferation to cytokine secretion and cell-mediated cytotoxicity. 5-HT is a classical neurotransmitter best known for its role in pain, appetite, sleep and mood. However, substantial evidence suggests that 5-HT may also play a role in modulation of host defense. Whether NKT cell responses are regulated by 5-HT is unknown and a subject of projects outlined in cluster II. In longer-term projects (cluster III), we will perform comprehensive multi-gene profiling of neurotransmitter receptors constitutively present or inducible in NKT cells. This will likely lead to numerous projects revolving around the overall theme of the proposed program in neuroimmune biology of NKT cells. We will also explore the influence of nervous system mediators on NKT cell responses to glycolipid antigens other than alpha-GalCer, cytokines produced by other immune cells (e.g., IL-12 and IL-18), and bacterial superantigens. Our studies will improve our understanding of NKT cell responses and their regulation at the neuroimmune interface. NKT cells? mode of recognition is evolutionarily conserved. Therefore, findings in mouse models are likely to be applicable to multiple mammalian species. The proposed program will enable the training of a future generation of scientists with a unique set of skills and expertise in an important, yet somewhat neglected area of biology.