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

Abstract

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.

Skin exposure promotes a Th2-dependent sensitization to peanut allergens

“…We and others have shown that OX40L on DCs is responsible for DC-mediated Th2 skewing and sensitization in the gastrointestinal tract (25,26,55). In the current studies, OX40L neutralization had only a minor inhibitory effect on DC-driven Th2 cytokine production in vitro and in vivo, indicating that other mechanisms for DC-driven Th2 priming must predominate in the skin.…”

Spatial regulation of IL-4 signalling in vivo

“…The activating dendritic cells do not provide decisive IL-4 [22]. Instead, it has been argued that Th2 induction results from a combination of antigen dose, select costimulatory molecules and the deliberate inhibition of conflicting signals, such as IL-12, that drive alternative T cell differentiation [19,[23][24][25][26][27]. Other innate cell types, such as basophils, may also enter the lymph node early in the immune response and provide polarising IL-4 signals [28][29][30][31].…”

The probiotic activity of Lactobacillus murinus against food allergy

“…The expression of OX40L was examined because it has been implicated in Th2-related allergic responses (Blázquez & Berin, 2008;Chu et al, 2014;Gauvreau et al, 2014). The mRNA expression of OX40L in the duodenum was enhanced in the OVA group ( Fig.…”

“…In addition to cytokine-dependent regulations, T cell differentiation is also influenced by co-stimulatory molecules expressed by dendritic cells (DC). For example, OX40 ligand (OX40L) has been linked to the development of Th2-related allergic responses (Blázquez & Berin, 2008;Chu et al, 2014;Gauvreau et al, 2014).…”