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Neurotransmitters associated with stress modulate invariant NKT cell responses in vivo

The following abstract was presented as part of London Health Research Day 2016.

Research Area: Molecular, Cellular, Infection, Immunity, and Cancer Biology
First Author: Patrick Rudak
Supervisor(s): Dr. Mansour Haeryfar

It is well recognized that stressful life events increase our susceptibilities to diseases such as infections, autoimmunity, and cancer. Studies over the past few decades have provided convincing evidence that stress-induced immunosuppression is consequential to these impacts on human health. Accordingly, it has been shown that mediators of stress can suppress conventional T cell-mediated immune responses, a crucial component of cellular immunity. However, whether these signals can influence immune responses mediated by non-conventional, invariant T cells remains poorly defined. Invariant natural killer T cells (iNKT cells) are a unique subset of T cells that rapidly secrete high levels of interferon-γ (IFN-γ) and interleukin-4 (IL-4) upon activation by glycolipid antigens including α-galactosylceramide (α-GalCer). Understanding how neural mediators of stress may influence early immune responses initiated by iNKT cells was the objective of this current study.

We hypothesized that neurotransmitters associated with stress will suppress cytokine responses initiated by iNKT cell activation.

Materials and Methods:
To address our hypothesis, we used norepinephrine (NE) and neuropeptide Y (NPY), two major neurotransmitters associated with stress which are released at sympathetic nerves innervating lymphoid organs. To observe their effects on iNKT cell-mediated cytokine responses in vivo, we challenged C57BL/6 mice intraperitoneally with α-GalCer in the presence or absence of NE or NPY and measured subsequent IFN-γ and IL-4 levels in the serum. To supplement these findings in vitro, we stimulated the DN32.D3 iNKT cell line with α-GalCer in the presence or absence of NPY or NE and measured subsequent cytokine levels in culture supernatants 24 hours later.

From our in vivo studies, we found striking suppression of systemic IFN-γ and early IL-4 production in the presence of NE. Similarly, NE suppresses iNKT cell function in vitro, significantly reducing cytokine secretion from iNKT cell activation in a dose dependent manner. In addition, our in vivo studies show that NPY significantly suppresses systemic IFN-γ production in mice challenged with α-GalCer, similar to the aforementioned effect mediated by NE.  However, unlike NE, NPY does not affect early in vivo IL-4 production of iNKT cell origin.

Discussion and Conculsions:
Taken together, we have demonstrated that mediators of stress can significantly impact iNKT cell responses in a largely suppressive manner, warranting future work to fully address this phenomenon. Future studies will include profiling neurotransmitter receptor gene expression by iNKT cells and using this data to extend our in vivo observations with selective receptor antagonists. In addition, our in vitro data will be extended using murine hepatic and splenic iNKT cells. Given the pivotal role of iNKT cells in linking innate and adaptive defense mechanisms, understanding how neural signals influence their function is of utmost importance.The overarching aim of this project is to uncover the impact of immunologically important neurotransmitters on several iNKT cell functions including activation, expansion, cytokine responses, and transactivation of other immune cell types.  This work will identify novel pathways linking the nervous system and the immune system and may reveal important implications in human health and disease.