Rapid up-regulation of CXC chemokines in the airways after Ag-specific CD4+ T cell activation.
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 alphabeta-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-alpha, 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.
Knott
P G
PG
Inflammatory Diseases Unit, Roche Bioscience, Palo Alto, CA 94304, USA.
Gater
P R
PR
Dunford
P J
PJ
Fuentes
M E
ME
Bertrand
C P
CP
D000280:Administration, Inhalation; D000281:Administration, Intranasal; D000336:Aerosols; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002464:Cell Migration Inhibition; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*
D000336:Aerosols; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D018984:Epitopes, T-Lymphocyte; D006133:Growth Substances; D007106:Immune Sera; D036341:Intercellular Signaling Peptides and Proteins; D010047:Ovalbumin