Signaling through Fc gamma RIII is required for optimal T helper type (Th)2 responses and Th2-mediated airway inflammation.
Although inhibitory Fc gamma receptors have been demonstrated to promote mucosal tolerance, the role of activating Fc gamma receptors in modulating T helper type (Th)2-dependent inflammatory responses characteristic of asthma and allergies remains unclear. Here, we demonstrate that signaling via activating Fc gamma receptors in conjunction with Toll-like receptor 4 stimulation modulated cytokine production from bone marrow-derived dendritic cells (DCs) and augmented their ability to promote Th2 responses. Ligation of the low affinity receptor Fc gamma RIII was specifically required for the enhanced Th2 responses, as Fc gamma RIII(-/-) DCs failed to augment Th2-mediated airway inflammation in vivo or induce Th2 differentiation in vitro. Further, Fc gamma RIII(-/-) mice had impaired Th2 cytokine production and exhibited reduced airway inflammation, whereas no defect was found in Fc gamma RI(-/-) mice. The augmentation of Th2 immunity was regulated by interleukin 10 production from the DCs but was distinct and independent of the well-established role of Fc gamma RIII in augmenting antigen presentation. Thus, our studies reveal a novel and specific role for Fc gamma RIII signaling in the regulation of Th cell responses and suggest that in addition to immunoglobulin (Ig)E, antigen-specific IgG also contributes to the pathogenesis of Th2-mediated diseases such as asthma and allergies.
Bandukwala
Hozefa S
HS
Committee on Immunology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Clay
Bryan S
BS
Tong
Jiankun
J
Mody
Purvi D
PD
Cannon
Judy L
JL
Shilling
Rebecca A
RA
Verbeek
J Sjef
JS
Weinstock
Joel V
JV
Solway
Julian
J
Sperling
Anne I
AI
D000818:Animals; D017951:Antigen Presentation; D001249:Asthma / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006967:Hypersensitivity / Q000378:metabolism; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D017452:Receptors, IgG; D051197:Toll-Like Receptor 4; D016753:Interleukin-10