Glucocorticoid and Adrenergic Receptor Signaling at the Neuroimmune Interface

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The nervous and the immune system work together to preserve our balance at molecular, cellular and organismal levels. To quickly deal with threats and stressors, a “fight-or-flight” response is mounted. This automatic and powerful response is characterized by the activation of the sympathetic nervous system (SNS) and by the release of hormones known as glucocorticoids (GCs) from the adrenal glands. SNS mediators and GCs are known to alter certain aspects of host defense, including conventional T (Tconv) cell responses. However, how stress, which activates the SNS and triggers GC release, affects unconventional immune cell types is ill-defined. These include natural killer T (NKT) cells and myeloid-derived suppressor cells (MDSCs). NKT cells are a unique subset of innate-like T lymphocytes. Unlike Tconv cells, NKT cells respond to glycolipids, molecules that are composed of sugar and fat, by rapidly secreting large quantities of soluble molecules called cytokines that mediate cell-to-cell communication in the immune system. This dictates the functions of numerous other cell types that participate in host defense. Therefore, it is pertinent to understand how NKT cell responses are initiated, perpetuated and regulated during stress. MDSCs are a diverse population of cells belonging to the myeloid lineage. They potently inhibit host responses to microbes, transformed cells and inflammatory cues. Therefore, their activities can be beneficial or detrimental to our homeostasis. Whether MDSC functions are controlled by mediators of the fight-or-flight response remains unexplored. In preliminary studies, we have found that stress due to physical confinement hinders the ability of mouse NKT cells to produce cytokines. In addition, restraint stress led to swift and robust accumulation of a cell population with similarities to MDSCs in the liver. The proposed program will address how the release of SNS mediators and GCs during stress influences NKT cell and MDSC functions. We have defined three project “clusters” within this interdisciplinary program. We will decipher the role(s) of SNS mediators and GCs on NKT cell survival and reactivity to glycolipids. We will reveal neurohormonal and immunological mechanisms underlying MDSC accumulation in the liver of stressed animals. Finally, we will extend our studies to other unconventional immune cell types and other models of stress with or without adaptation to GCs. The proposed program will improve our understanding of cellular and molecular cross-talk at the neuroimmune interface, and will elucidate how NKT cells and MDSCs are impacted by a fight-or-flight response. Our studies may generate novel and potentially marketable products, models or strategies for studying and/or manipulating unconventional immune responses. Equally important, this program will enable the training of a future generation of highly sought-after experts in the important, yet somewhat neglected, area of neuroimmune biology.