Allergic humans are hypo‐responsive to CXCR3 chemokines in a Th1 immunity‐promoting loop

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Abstract
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 IFNγ production by healthy and allergic individuals characterized by Th1 and Th2 immunity- dominated allergen specific responses, respectively. Exogenous CXCR3 ligands up-regulated antigen-dependent IFNγ 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 IFNγ 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.
Funding Information
  • Canadian Institutes of Health Research