HUMAN IP-10 SELECTIVELY PROMOTES DOMINANCE OF POLYCLONALLY ACTIVATED AND ENVIRONMENTAL ANTIGEN-DRIVEN IFN-GAMMA OVER IL-4 RESPONSES

Human interferon-inducible protein 10 (IP-10) differs from most chemok ines in its apparent specificity for activated T lymphocytes, We hypot hesized that LP-10 was relevant not only for recruiting T cells to inf lammatory sites, but also for regulating cytokine synthesis patterns. We examined the effect of recombinant human LP-10 (rhIP-10) on human i nterferon gamma (IFN-gamma) and interleukin 4 (IL-4) production by fre sh peripheral blood mononuclear cells. We demonstrate for the first ti me that this CXC chemokine selectively up-regulates human T cell cytok ine synthesis, with enhancement selectively targeted to promotion of T h1-like dominance. Superantigen (TSST-1), soluble anti-CD3 mAb, and ph ytohemagglutinin were used to activate distinct intracellular signalin g pathways, thereby inducing quantitatively different IFN-gamma:IL-4 r atios. Selective enhancement of IFN-gamma responses was consistently o bserved, with median increases of 105-470%. Environmental antigens (Ag ) were used to evaluate IP-10's effect on CD4-dependent, chloroquine-s ensitive cytokine synthesis. Ag-driven IFN-gamma responses exhibited m edian 19- to 30-fold increases in the presence of nanomolar concentrat ions of rhIP-10, IL-4 responses were neither enhanced nor inhibited un der any of the conditions tested. These findings suggest a potential r ole for this T cell-focused chemokine in maintenance of the default Th 1-like responses usually seen to environmental Ag and indicate a poten tial application in the modulation of Ag-driven responses in vivo.