Signal Transducer and Activator of Transcription 6 Controls Chemokine Production and T Helper Cell Type 2 Cell Trafficking in Allergic Pulmonary Inflammation

doi:10.1084/jem.193.9.1087

Published online 7 May 2001.

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© The Rockefeller University Press, 0022-1007/2001/5/1087/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 9, May 7, 2001 1087-1096

Original Article

Signal Transducer and Activator of Transcription 6 Controls Chemokine Production and T Helper Cell Type 2 Cell Trafficking in Allergic Pulmonary Inflammation

Anuja Mathew^a, James A. MacLean^a, Elliot DeHaan^a, Andrew M. Tager^a, Francis H.Y. Green^b, and Andrew D. Luster^a

^a Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
^b Department of Pathology, University of Calgary, Calgary, Alberta, Canada T2N 1N4
Massachusetts General Hospital, Bldg. 149, 13th St., Charlestown, MA 02129.617-726-5651617-726-5710

luster{at}helix.mgh.harvard.edu

Antigen-specific CD4 T helper type 2 (Th2) cells play a pivotalrole in the induction of allergic asthma, but the mechanismsregulating their recruitment into the airways are unknown. Signaltransducer and activator of transcription factor (Stat)6 isa transcription factor essential for Th2 cell differentiation.Here we show that Stat6 also controls Th2 cell recruitment andeffector function in allergic inflammation in vivo. To isolatethe role of Stat6 in regulating Th2 cell trafficking and effectorfunction from its role in Th2 cell differentiation, we useda murine model of asthma in which in vitro–differentiatedStat6^+/+ antigen-specific Th2 cells were adoptively transferredinto naive Stat6^–/– and Stat6^+/+ mice followed byaerosol antigen challenge. We found that all of the featuresof asthma, including Th2 cell accumulation, Th2 and eosinophil-activechemokine production, and airway eosinophilia, mucus production,and hyperresponsiveness seen in Stat6^+/+ mice, were dramaticallyabsent in Stat6^–/– mice that received Stat6^+/+ antigen-specificTh2 cells. Our findings establish Stat6 as essential for Th2cell trafficking and effector function and suggest that interruptionof Stat6 signaling in resident cells of the lung is a novelapproach to asthma therapy.

Key Words: asthma • cytokines • eosinophil • transcription factor • knockout mouse

Abbreviations used in this paper: AHR, airway hyperresponsiveness;BAL, bronchoalveolar lavage; CCR, CC chemokine receptor; MDC,macrophage-derived chemokine; PAS, periodic acid-Schiff; RPA,RNase protection assay; Stat, signal transducer and activationof transcription; TARC, thymus- and activation-regulated chemokine;TCA, thymus-derived chemotactic agent; VCAM, vascular cell adhesionmolecule.

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