Adrenal steroids are important effector hormones in neuroendocrine-immune interactions and may be involved in a number of key immune processes which are relevant to the host immune response to viral infections, including AIDS. To further understand the role of adrenal steroids in immune regulation, over the past several years our laboratories have focused on the receptors for adrenal steroid hormones in immune cells and tissues. Our data indicates that the expression and activation of adrenal steroid receptors are critical factors in determining when and in which immune cells and tissues adrenal steroids are capable of modulating the immune response. Recently, we have applied our understanding of adrenal steroid- immune system interactions from the perspective of the receptor to a well- characterized animal model of a viral infection. Specifically, we have examined adrenal steroid secretion and adrenal steroid receptors in mice infected with lymphocytic choriomeningitis virus (LCMV); an RNA virus primarily cleared by virus-specific cytotoxic T lymphocytes (CTLs). Interestingly, we discovered significant decreases in adrenal steroid receptors in the mouse spleen on day 7 post infection, a time which corresponds with the peak in CTL activity. In addition, we found significant elevations in circulating corticosterone. Based on our findings from the previous project period, receptor decreases in the context of elevated adrenal steroids suggests that adrenal steroid hormones are activating their receptors in the cells of the spleen, and therefore are in a position to modulate CTL activity following LCMV infection. The factors which negatively regulate CTL activity once activated have not been determined, and since adrenal steroids have well known inhibitory effects on a wide range of immune processes, evidence of adrenal steroid receptor activation at the time of peak CTL activity suggests that adrenal steroids may be involved in the negative regulation of CTL function. The long term objectives of the proposed work are to further examine the role of endogenous adrenal steroids in the modulation of specific immune responses during a viral infection.
The specific aims of this project are to test the hypothesis that adrenal steroids play an important role in feedback inhibition of CTL activity following LCMV infection. To this end, we will determine 1) if LCMV is associated with increased adrenal steroid secretion (Specific Aim 1), 2) whether increased adrenal steroid secretion is associated with adrenal steroid receptor activation in relevant target tissues and cells (Specific Aims 2, 3 and 4), 3) whether adrenal steroid receptor activation is associated with specific immune cell functions relevant to CTL activity (Specific Aim 5), and 4) if removal or administration of corticosterone respectively, enhances or inhibits, specific immune functions which are relevant to CTL activity and virus replication (Specific Aim 6). The proposed studies represent one of the first critical examinations of the role of endogenous adrenal steroids in the evolution of an immune response after viral infection. The information gained will provide important data as to which immune responses are modulated by hormones and when, thereby indicating relevant entry points where brain and behavioral factors may influence immune regulation and ultimately the development of viral diseases.
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