The long-term goal of this research is to identify the mechanisms that underlie the immunomodulatory effects of opioids and to understand their role in health and disease. Expression of opioid receptors by cells of the immune system makes them subject to modulation by opiate drugs and to endogenous opioid peptides which are synthesized within the immune system as well by the pituitary. Extensive evidence for opioid modulation of immune function in in vitro assays indicates that opioid Immunomodulation likely has important clinical consequences. The appropriate polarization of T cells to effectors, which secrete distinct panels of cytokines is critical for mounting effective immune responses. A strong T1 cytokine response inCD8+ T cells is correlated with HIV specific immunity and repressed viral replication but may also contribute to transmission of the virus. In the current grant, methionine enkephalin (Menk), an endogenous delta opioid receptor (dOR) selective opioid peptide, has been shown to polarize CD8+ Tcells towards a T(c)l phenotype. And, the T cell CD28 co-receptor has been shown to play an important role in inducing dOR expression in both CD4+ and CD8+ T cells. DOR expression in dendritic cells also has been found. In Aim 1 of this proposal, the intracellular MAPK signaling pathways responsible forCD28 T cell co-receptor dependent induction of dOR expression and its subsequent down regulation will be investigated in murine T cells. The role of the sphingomyelinase signaling pathways in regulating dOR expression will be examined in Aim 2. Based on the expression of dORs in both T cells and antigen presenting cells (APC) at the time that Menk addition modulates polarization. We hypothesize that opioid modulation of APC T cell interactions during initial T cell activation results in the polarizing activity. To identify the mechanisms responsible, the effects of Menk and dOR selective agonists on the expression of initial polarizing cytokines (Aim3) and chemokines (Aim 4) will be examined during initial T cell activation in a mouse model system. Menk and dOR dependent modulation of viral clearance in a CD8+T cell and IFNg dependent murine model will be used to test the physiological relevance of in vitro findings in Aim 5.