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Naïve T cells, when activated by specific antigen and cytokines, up-regulate adhesion molecules as well as chemokine receptors on their surface, which allows them to migrate to inflamed tissues. Human studies have shown that CXCR3 is one of the chemokine receptors that is induced during T cell activation. Moreover, CXCR3-positive T cells are enriched at inflammatory sites in patients with autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. In this study, we use a mouse model of inflammation to demonstrate that CXCR3 is required for activated T cell transmigration to inflamed tissue. Using an anti- mCXCR3 antibody, we have shown that in vitro-differentiated T helper (Th) 1 and Th2 cells up-regulated CXCR3 upon stimulation with specific antigen/major histocompatibility complex. However, only Th1 cells, when adoptively transferred to syngeneic recipients, are efficiently recruited to the peritoneum in an adjuvant-induced peritonitis model. Furthermore, the neutralizing anti-mCXCR3 antibody profoundly inhibits the recruitment of Th1 cells to the inflamed peritoneum. Real-time, quantitative reverse transcriptase-polymerase chain reaction analysis demonstrates that the CXCR3 ligands, interferon (IFN)-inducible protein 10 (CXCL10) and IFN-inducible T cell alpha chemoattractant (CXCL11), are among the many chemokines induced in the adjuvant-treated peritoneum. The anti-mCXCR3 antibody is also effective in inhibiting a delayed-type hypersensitivity response, which is largely mediated by enhanced trafficking of activated T cells to peripheral inflammatory sites. Collectively, our results suggest that CXCR3 has a critical role in T cell transmigration to sites of inflammation and thus, may serve as a molecular target for anti-inflammatory therapies.

Original publication

DOI

10.1189/jlb.1102573

Type

Journal article

Journal

Journal of leukocyte biology

Publication Date

06/2003

Volume

73

Pages

771 - 780

Addresses

Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey 07065, USA. Jenny_xie@merck.com

Keywords

Peritoneum, Th1 Cells, Th2 Cells, Cells, Cultured, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Peritonitis, Hypersensitivity, Delayed, Inflammation, Receptors, Chemokine, Freund's Adjuvant, Antibodies, Antigens, Ligands, Adoptive Transfer, Chemotaxis, Leukocyte, Genes, T-Cell Receptor, Receptors, CXCR3