CXCR3-mediated opposite effects of CXCL10 and CXCL4 on TH1 or TH2 cytokine production

Background: Two variants of the CXCR3 receptor exist, one (CXCR3-A) reactive with CXCL9, CXCL10, and CXCL11 and the other (CXCR3-B) also reactive with CXCL4. Both variants are contemporarily expressed by human T cells. Objective: We sought to investigate the in vitro effects of CXCL10 and CXCL4 on the production of T_H1 or T_H2 cytokines. Methods: The cytokine profile of antigen-specific human CD4⁺ T-cell lines obtained in the absence or presence of CXCL10 or CXCL4 was evaluated by means of quantitative RT-PCR, flow cytometry, and ELISA. Results: CXCL10 upregulated IFN-γ and downregulated IL-4, IL-5, and IL-13 production, whereas CXCL4 downregulated IFN-γ and upregulated T_H2 cytokines. Similar effects were also observed on polyclonally activated pure naive CD4⁺ T cells. The opposite effects of CXCL10 and CXCL4 on T_H1 and T _H2 cytokine production were inhibited by an anti-CXCR3 antibody able to neutralize both CXCR3-A and CXCR3-B and were apparently related to the activation of distinct signal transduction pathways. Moreover, CXCL10 upregulated mRNA levels of T-box expressed in T cells and downregulated GATA-3 expression, whereas CXCL4 downregulated T-box expressed in T cells and upregulated GATA-3. Finally, CXCL4, but not CXCL10, induced direct activation of IL-5 and IL-13 promoters. Conclusion: CXCL10 and CXCL4 exert opposite effects on the production of human T_H1 and T_H2 cytokines, likely through their respective interaction with CXCR3-A or CXCR3-B and the consequent activation of different signal transduction pathways. This might represent an internal regulatory pathway of T_H cell responses and might contribute to the modulation of chronic inflammatory reactions, including allergy.