CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation.
T helper 2 (Th2) cells play a critical role in the pathogenesis of asthma, but the precise immunological mechanisms that inhibit Th2 cell function in vivo are not well understood. Using gene therapy, we demonstrated that ovalbumin-specific (OVA-specific) Th cells engineered to express latent TGF-beta abolished airway hyperreactivity and airway inflammation induced by OVA-specific Th2 effector cells in SCID and BALB/c mice. These effects correlated with increased concentrations of active TGF-beta in the bronchoalveolar lavage (BAL) fluid, demonstrating that latent TGF-beta was activated in the inflammatory environment. In contrast, OVA-specific Th1 cells failed to inhibit airway hyperreactivity and inflammation in this system. The inhibitory effect of TGF-beta-secreting Th cells was antigen-specific and was reversed by neutralization of TGF-beta. Our results demonstrate that T cells secreting TGF-beta in the respiratory mucosa can indeed regulate Th2-induced airway hyperreactivity and inflammation and suggest that TGF-beta-producing T cells play an important regulatory role in asthma.
Hansen
G
G
Division of Immunology, Department of Pediatrics, Stanford University, Stanford, California 94305, USA.
McIntire
J J
JJ
Yeung
V P
VP
Berry
G
G
Thorbecke
G J
GJ
Chen
L
L
DeKruyff
R H
RH
Umetsu
D T
DT
D000485:Allergens / Q000276:immunology*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002460:Cell Line; D004802:Eosinophilia / Q000517:prevention & control; D015316:Genetic Therapy; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000628:therapy*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D000485:Allergens; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D010047:Ovalbumin