Antibody-mediated blockade of the CXCR3 chemokine receptor results in diminished recruitment of T helper 1 cells into sites of inflammation
2003
Naive T cells, when activated by specific antigen and cytokines, up-regulate adhesion mole- cules 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 en- riched at inflammatory sites in patients with autoim- mune diseases such as rheumatoid arthritis and mul- tiple 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 synge- neic recipients, are efficiently recruited to the peri- toneum in an adjuvant-induced peritonitis model. Furthermore, the neutralizing anti-mCXCR3 anti- body 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, inter- feron (IFN)-inducible protein 10 (CXCL10) and IFN- inducible T cell chemoattractant (CXCL11), are among the many chemokines induced in the adju- vant-treated peritoneum. The anti-mCXCR3 anti- body is also effective in inhibiting a delayed-type hy- persensitivity 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 transmigra- tion to sites of inflammation and thus, may serve as a molecular target for anti-inflammatory therapies. J. Leukoc. Biol. 73: 771-780; 2003.
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