Human IP‐10 selectively promotes dominance of polyclonally activated and environmental antigen‐driven IFN‐γ over IL‐4 responses

Abstract

Human interferon-inducible protein 10 (IP-10) differs from most chemokines in its apparent specificity for activated T lymphocytes. We hypothesized that IP-10 was relevant not only for recruiting T cells to inflammatory sites, but also for regulating cytokine synthesis patterns. We examined the effect of recombinant human IP-10 (rhIP-10) on human interferon gamma (IFN-gamma) and interleukin 4 (IL-4) production by fresh peripheral blood mononuclear cells. We demonstrate for the first time that this CXC chemokine selectively up-regulates human T cell cytokine synthesis, with enhancement selectively targeted to promotion of Th1-like dominance. Superantigen (TSST-1), soluble anti-CD3 mAb, and phytohemagglutinin were used to activate distinct intracellular signaling pathways, thereby inducing quantitatively different IFN-gamma:IL-4 ratios. Selective enhancement of IFN-gamma responses was consistently observed, with median increases of 105-470%. Environmental antigens (Ag) were used to evaluate IP-10's effect on CD4-dependent, chloroquine-sensitive cytokine synthesis. Ag-driven IFN-gamma responses exhibited median 19- to 30-fold increases in the presence of nanomolar concentrations of rhIP-10. IL-4 responses were neither enhanced nor inhibited under any of the conditions tested. These findings suggest a potential role for this T cell-focused chemokine in maintenance of the default Th1-like responses usually seen to environmental Ag and indicate a potential application in the modulation of Ag-driven responses in vivo.

Markers of Innate Immune Function Are Associated with Vitamin A Stores in Men

“…Elevated serum IP10 concentrations are seen in Yellow Fever patients (42) and the IP10 response in this study may be due largely to the Th1-inducing effects of the live-virus YFV vaccine (43,44), although a role for the inactivated TT vaccine is also plausible. The increased serum IP10 in the high VA group is interesting, because, in addition to being a chemotactic factor for inflammatory cells, IP10 also promotes IFNg responses by Th1 cells (45). This finding supports our previous observation that normal vitamin A status helps promote a Th1 response relative to the response in deficient mice (46).…”

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

“…This suggests that there is a T cell–intrinsic feedback loop for CXCL10 production, and that the low level of CXCL10 produced by the DCs may require the IFNγR‐mediated T cell feedback loop as well (Fig 5). CXCL10 and the CXCR3 receptor have been proposed to work in an inflammation‐promoting loop in allergy27 and to modulate IFNγ production in EAE 28. CXCR3 has been suggested not only to play a role in T cell priming in the lymph node24 but also in the recruitment of T cells into peripheral target tissues 29.…”

CXCR3-Dependent Recruitment of Antigen-Specific T Lymphocytes to the Liver during Murine Cytomegalovirus Infection

“…Additional findings describe a role for CXCL9 (55) and CXCL10 (7) in stimulating the effector functions of CXCR3-expressing leukocytes, cytokine production, and promotion of T-cell proliferation, suggesting that chemokines can function in a manner similar to that of T-lymphocyte costimulatory molecules. Furthermore, CXCL10 has been shown to modulate cytokine release from peripheral blood mononuclear cell cultures following stimulation with environmental antigens (9). In the liver, elevated levels of CXCL10 have been associated with reductions in liver injury and tissue regeneration (3,16).…”