Neural and behavioral responses to systemic immunologic stimuli: a consideration of bacterial T cell superantigens

Immune responses represent a source of systemic stress which impacts the brain and modifies various neuroendocrine and behavioral functions. Therefore, the immune system has been conceived of as a potential contributor to stress-related behavioral abnormalities, such as depression. Much of this knowledge has been gained through research focused largely on the administration of cytokines and/or bacterial endotoxin (eg., LPS), which targets innate immune cells, such as macrophages. However, fewer studies have addressed the effects of T cell activation on central nervous system (CNS) function. The discovery and characterization of bacterial superantigens (SAgs) has introduced an important opportunity for studying how T cell activation influences CNS function. Superantigens target unique variable regions of the beta chain of the mouse and human T cell receptor. This is restricted by the class II molecule of the major histocompatibility complex (MHC), and results in the production of a cytokine cascade that includes interleukin-2 (IL-2), interferon-gamma (IFNgamma), tumor necrosis factor (TNF) and many other cytokines, including IL-6. The best studied SAgs are the staphylococcal enterotoxins, of which staphylococcal enterotoxins A and B (SEA and SEB), have been shown to produce significant changes in behavior and activation of the hypothalamic-pituitary-adrenal (HPA) axis. Importantly, a T cell requirement was necessary to produce these changes. Furthermore, the anorexic or hypophagic effects of SAg challenge in mice appears to be related to anxiety-like processes, since challenge with both SEA or SEB reduces consumption of mainly novel food or food presented in a novel context. In the present paper, these studies are reviewed and related to known alterations in both anxiogenic and anxiolytic neuropeptides. It is suggested that immunologically-induced changes in the brain activate both categories of neuropeptides, thereby sustaining an adaptive state of arousal that promotes appropriate behavioral adjustments during infectious illness.