Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 116, Issue 6, Pages 1372-1379Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2005.09.035
Keywords
CXCR3; T(H)1; T(H)2; CXCL10; CXCL4; GATA-3; T-bet; immune deviation
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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(H)1 or T(H)2 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-gamma and downregulated IL-4, IL-5, and IL-13 production, whereas CXCL4 downregulated IFN-gamma and upregulated TH2 cytokines. Similar effects were also observed on polyclonally activated pure naive CD4+ T cells. The opposite effects of CXCL10 and CXCL4 on TH1 and TH2 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 TH1 and TH2 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.
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