IgE regulates T helper cell differentiation through FcgammaRIII mediated dendritic cell cytokine modulation - PubMed (original) (raw)

IgE regulates T helper cell differentiation through FcgammaRIII mediated dendritic cell cytokine modulation

Sarah E Blink et al. Cell Immunol. 2010.

Abstract

Asthma and allergy are characterized by dysregulation of inflammatory responses toward Th2 responses and high serum levels of IgE. IgE plays a role in the effector phase by triggering the degranulation of mast cells after antigen-crosslinking but its role in the induction of helper T cell differentiation is unknown. We have previously shown lymphotoxin is required for maintaining physiological levels of serum IgE which minimize spontaneous Th1-mediated airway inflammation, suggesting a physiological role for IgE in the regulation of T helper cell differentiation. We describe the mechanism in which IgE modulates inflammation by regulating dendritic cell cytokine production. Physiological levels of IgE suppress IL-12 production in the spleen and lung, suggesting IgE limits Th1 responses in vivo. IgE directly stimulates dendritic cells through FcgammaRIII to suppress IL-12 in vitro and influences APC to skew CD4+ T cells toward Th2 differentiation. We demonstrate a novel role for IgE in regulating differentiation of adaptive inflammatory responses through direct interaction with FcgammaRIII on dendritic cells.

2010 Elsevier Inc. All rights reserved.

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Figures

Fig 1

Fig 1

IgE suppresses IL-12 production in vivo and in vitro. (A) Splenocytes and cells from collagenase digested lung from 12 week old WT and LT−/− mice were stimulated with LPS for 24 hours. After 24 hours supernatant was collected and subjected ELISA to measure IL-12p70. *** P<0.0001, ** P=0.0007 and * P<0.040. (B) APC from RAG-1−/− spleens and LN were sensitized with or without 5 ug/ml anti-DNP IgE on DNP-HSA coated plates. After 24 hours supernatant was collected and subjected ELISA to measure IL-12p70. Data are reported as a mean and representative of at least 4 experiments where *** P<0.0004 and ** P=0.0010.

Fig 2

Fig 2

IgE influences APC to promote Th2 differentiation. APC from RAG-1−/− spleens and LN were sensitized with or without 5 ug/ml anti-DNP IgE on DNP-HSA coated plates. After 24 hours of sensitization, purified CD4+ OTII T cells to APC with OVAp. After priming, live cells were normalized for cell number and restimulated with anti-CD3. After 48 hours restimulation, the supernatant was collected and subjected to CBA for cytokine quantification (A). T cell differentiation was determined by a ratio of [IFN-γ]: [IL-4] (B). Data are representative of at leaset 3 experiments where ** P=0.0026 for untreated (media) vs. IgE crosslinked (DNP+ IgE).

Fig 3

Fig 3

IgE mediates cytokine modulation via an FcγR from dendritic cells. APC from RAG1−/− spleens and LN were sensitized with or without 5 ug/ml anti-DNP IgE on DNP-HSA coated plates and stimulated with LPS and for some samples increasing amounts of soluble 2.4G2. After 24 hours incubation, supernatant was collected and IL-12 p70 was measured by ELISA. Data are reported as mean ± SEM and representative of 3 experiments where *** P<0.0003 and ns P=0.0594.

Fig 4

Fig 4

IgE mediated DC cytokine regulation requires FcγRIII. Bone marrow derived dendritic cells were derived from WT, FcεRγ−/− and FcγRIII−/− bone marrow with GM-CSF. BMDC were sensitized with or without 5 ug/ml anti-DNP IgE on DNP-HSA coated plates and stimulated with LPS. After 24 hours incubation, supernatant was collected and IL-12 p70 was measured by ELISA. Data are reported as mean ± SEM and representative of 2 experiments where ** P=0.0054 and * P=0.014.

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