Allergic humans are hyporesponsive to a CXCR3 ligand-mediated Th1 immunity-promoting loop.
CXCR3 binding chemokine CXCL10 (IP-10) markedly enhances antigen-specific Th1 recall responses in healthy humans, suggesting a role for this pathway in maintenance of clinical tolerance to environmental allergens as well as a potential therapeutic role for CXCR3 ligands in re-balancing the Th2-dominated responses that underlie generation and maintenance of allergic disorders. Here, we investigated the capacity of CXCR3 ligands to modulate allergen-driven IFNgamma production by healthy and allergic individuals characterized by Th1 and Th2 immunity-dominated allergen specific responses, respectively. Exogenous CXCR3 ligands up-regulated antigen-dependent IFNgamma production from healthy individuals' peripheral blood mononuclear cells up to 120-fold, a response neutralized by anti-CXCR3 treatment and not emulated by CCR5 ligands. In contrast, allergic individuals were strikingly hypo-responsive to CXCR3 ligands (P=0.0004). Chemokine-enhanced IFNgamma production correlated with T cell CXCR3 expression (r=0.736, P=0.0001) in vivo and was independent of Th2 cytokine levels. These findings demonstrate that CXCR3-ligation preferentially augments ongoing Th1 over Th2 responses and suggest that reduced capacity of allergic individuals to respond to CXCR3 ligands promotes the maintenance of human allergic disorders.
Campbell
J Darren
JD
CIHR National Training Program in Allergy and Asthma Research, Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
Gangur
Venu
V
Simons
F Estelle R
FE
HayGlass
Kent T
KT
D000485:Allergens / Q000276:immunology; D000818:Animals; D002415:Cats; D002478:Cells, Cultured; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology; D008024:Ligands; D018448:Models, Immunological; D006109:Poaceae / Q000276:immunology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D000485:Allergens; C515187:CXCR3 protein, human; D008024:Ligands; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D016753:Interleukin-10; D007371:Interferon-gamma