T helper cell IL-4 drives intestinal Th2 priming to oral peanut antigen, under the control of OX40L and independent of innate-like lymphocytes

Mucosal Immunol. 2014 Nov;7(6):1395-404. doi: 10.1038/mi.2014.29. Epub 2014 Apr 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / chemistry
  • Allergens / immunology*
  • Animals
  • Arachis / chemistry*
  • Eosinophils / immunology
  • Eosinophils / pathology
  • Immunity, Innate
  • Immunoglobulin E / immunology
  • Immunoglobulin G / immunology
  • Interleukin-13 / genetics
  • Interleukin-13 / immunology
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology*
  • Intestines / immunology*
  • Intestines / pathology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Mice
  • Mice, Knockout
  • OX40 Ligand
  • Peanut Hypersensitivity / immunology*
  • Peanut Hypersensitivity / pathology
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • Th2 Cells / immunology*
  • Th2 Cells / pathology
  • Tumor Necrosis Factors / genetics
  • Tumor Necrosis Factors / immunology*


  • Allergens
  • Immunoglobulin G
  • Interleukin-13
  • Membrane Glycoproteins
  • OX40 Ligand
  • Receptors, Antigen, T-Cell, gamma-delta
  • Tnfsf4 protein, mouse
  • Tumor Necrosis Factors
  • Interleukin-4
  • Immunoglobulin E