T helper cell IL-4 drives intestinal Th2 priming to oral peanut antigen, under the control of OX40L and independent of innate-like lymphocytes.
Intestinal T helper type 2 (Th2) immunity in food allergy results in IgG1 and IgE production, and antigen re-exposure elicits responses such as anaphylaxis and eosinophilic inflammation. Although interleukin-4 (IL-4) is critically required for allergic sensitization, the source and control of IL-4 during the initiation of Th2 immunity in vivo remains unclear. Non-intestinal and non-food allergy systems have suggested that natural killer-like T (NKT) or γδ T-cell innate lymphocytes can supply the IL-4 required to induce Th2 polarization. Group 2 innate lymphoid cells (ILCs) are a novel IL-4-competent population, but their contribution to initiating adaptive Th2 immunity is unclear. There are also reports of IL-4-independent Th2 responses. Here, we show that IL-4-dependent peanut allergic Th2 responses are completely intact in NKT-deficient, γδ T-deficient or ILC-deficient mice, including antigen-specific IgG1/IgE production, anaphylaxis, and cytokine production. Instead, IL-4 solely from CD4(+) Th cells induces full Th2 immunity. Further, CD4(+) Th cell production of IL-4 in vivo is dependent on OX40L, a costimulatory molecule on dendritic cells (DCs) required for intestinal allergic priming. However, both Th2 cells and ILCs orchestrated IL-13-dependent eosinophilic inflammation. Thus, intestinal Th2 priming is initiated by an autocrine/paracrine acting CD4(+) Th cell-intrinsic IL-4 program that is controlled by DC OX40L, and not by NKT, γδ T, or ILC cells.
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
D K
DK
Chu
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
Z
Z
Mohammed-Ali
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
R
R
Jiménez-Saiz
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
T D
TD
Walker
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
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S
Goncharova
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
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A
Llop-Guevara
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
J
J
Kong
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
M E
ME
Gordon
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
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NG
Barra
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
A E
AE
Gillgrass
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
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H
Van Seggelen
Departments of Pathology and Molecular Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
W I
WI
Khan
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
A A
AA
Ashkar
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
J L
JL
Bramson
Departments of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, USA.
A A
AA
Humbles
Departments of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, USA.
R
R
Kolbeck
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
S
S
Waserman
Departments of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
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M
Jordana
D000485:Allergens / Q000737:chemistry / Q000276:immunology*; D000818:Animals; D010367:Arachis / Q000737:chemistry*; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate; D007073:Immunoglobulin E / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053278:OX40 Ligand; D021183:Peanut Hypersensitivity / Q000276:immunology* / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology*
D000485:Allergens; D007074:Immunoglobulin G; D018793:Interleukin-13; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D016692:Receptors, Antigen, T-Cell, gamma-delta; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D015847:Interleukin-4; D007073:Immunoglobulin E