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Rapid Up-Regulation of CXC Chemokines in the Airways after Ag-Specific CD4⁺ T Cell Activation

Inflammatory Diseases Unit, Roche Bioscience, Palo Alto, CA 94304

Ag-specific activation of CD4⁺ T cells is known to be causative for the cytokine production associated with lung allergy. Chemokine-induced leukocyte recruitment potentially represents a critical early event in Ag-induced lung inflammation. Whether Ag-specific, lung CD4⁺ T cell activation is important in lung chemokine production is currently not clear. Using -TCR transgenic BALB/c DO11.10 mice, we investigated the ability of Ag-specific CD4⁺ T cell activation to induce lung chemokine production and leukocyte recruitment. Within 1 h of exposure of DO11.10 mice to OVA aerosol, lung mRNA and protein for the neutrophil chemokines KC and macrophage inflammatory protein (MIP)-2 were greatly increased. Accordingly, neutrophils in the airways increased by >50-fold, and KC and MIP-2 proved to be functional because their neutralization significantly reduced airway neutrophilia. CD4⁺ T cell activation was critical because CD4⁺ but not CD8⁺ T cell depletion reduced KC production, which correlated well with the previously observed inhibition of neutrophil influx after CD4⁺ T cell depletion. In vitro studies confirmed that OVA-induced KC and MIP-2 production was conditional upon the interaction of CD4⁺ T cells with APCs. A likely secondary mediator was TNF-, and a probable source of these chemokines in the lung was alveolar macrophages. Thus, Ag-specific CD4⁺ T cell activation in the lung leads to rapid up-regulation of neutrophil chemokines and the recruitment of neutrophils to the site of Ag exposure. This may be a key early event in the pathogenesis of Ag-induced lung inflammation.

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