Understanding the development of Th2 cell-driven allergic airway disease in early life

Abstract

Allergic diseases, including atopic dermatitis, allergic rhinitis, asthma, and food allergy, are caused by abnormal responses to relatively harmless foreign proteins called allergens found in pollen, fungal spores, house dust mites (HDM), animal dander, or certain foods. In particular, the activation of allergen-specific helper T cells towards a type 2 (Th2) phenotype during the first encounters with the allergen, also known as the sensitization phase, is the leading cause of the subsequent development of allergic disease. Infants and children are especially prone to developing Th2 cell responses after initial contact with allergens. But in addition, the rates of allergic sensitization and the development of allergic diseases among children are increasing in the industrialized world and have been associated with living in urban settings. Particularly for respiratory allergies, greater susceptibility to developing allergic Th2 cell responses has been shown in children living in urban environments containing low levels of microbial contaminants, principally bacterial endotoxins [lipopolysaccharide (LPS)], in the causative aeroallergens. This review highlights the current understanding of the factors that balance Th2 cell immunity to environmental allergens, with a particular focus on the determinants that program conventional dendritic cells (cDCs) toward or away from a Th2 stimulatory function. In this context, it discusses transcription factor-guided functional specialization of type-2 cDCs (cDC2s) and how the integration of signals derived from the environment drives this process. In addition, it analyzes observational and mechanistic studies supporting an essential role for innate sensing of microbial-derived products contained in aeroallergens in modulating allergic Th2 cell immune responses. Finally, this review examines whether hyporesponsiveness to microbial stimulation, particularly to LPS, is a risk factor for the induction of Th2 cell responses and allergic sensitization during infancy and early childhood and the potential factors that may affect early-age response to LPS and other environmental microbial components.

Keywords: GM-CSF; IL-12 cytokine; IL-2 cytokine; LPS (lipopolysaccharide); T-bet; Th2 cells; dendritic cells; infants.

Figure 1

Mechanisms that promote and prevent Th2 cell responses to allergens. Promotion of Th2 cell responses: allergens with proteolytic activity, cytokines, and microbial products, such as LPS, can activate epithelial cells for subsequent release of the cytokines GM-CSF, TSLP, IL-33, and IL-25. This leads to the activation of ILC2s and the release of IL-13. GM-CSF and IL-13 stimulate the migration and expression of the transcription factors IRF4, KLF4, and STAT6 in cDC2s, ultimately promoting the functional specialization of the cDC2s to support Th2 cell differentiation by reducing the ability of the cDC2s to produce IL-12, while retaining their co-stimulatory ability to foster strong IL-2 responses in CD4⁺ T cells. Strong and sustained IL-2 signaling in the absence of IL-12 promotes Th2 cell lineage commitment by promoting the expression of IL-4Rα and IL-4, allowing for an IL-4-positive feedback loop that initiates and preserves the Th2 cell phenotype. Prevention of Th2 cell responses: allergens with cysteine protease activity stimulate GM-CSF release from perivascular Ly6C^lo non-classical monocytes, guiding the differentiation of Ly6C^hi classical monocytes into moDCs. GM-CSF licenses an inflammatory signature in moDCs by increasing the expression of TLR4, CD14, and intracellular signaling members involved in the MyD88/NF-kB/AP-1-dependent pathway. Functional programming of moDCs by GM-CSF allows these cells to increase their sensitivity to LPS and stimulate the production of the pro-inflammatory cytokine TNFα, which guides cDC2 activation for Th2 cell suppression rather than promotion. In particular, TNFα induces the expression of the transcription factor T-bet in cDC2s, which is intrinsically necessary for the ability of cDC2s to produce sustained IL-12 and suppress Th2 cell priming by inducing T-bet and inhibiting GATA3 in CD4⁺ T cells. cDC2s can also produce IL-6, upregulating SOCS3 in CD4⁺ T cells and ultimately suppressing IL-2 signaling and early Th2 cell commitment. cDC1s and moDCs are additional sources of IL-12 that contribute to the suppression of Th2 cell responses.

Figure 2

Steps toward generating effector Th2 cell responses to allergens. During the sensitization phase, cDC2s prime allergen-specific Tfh2 cell responses in the draining lymph node. Through interactions with B cells, Tfh2 cells promote IgE secretion. Following allergen re-exposure, Tfh2 cells differentiate into effector Th2 cells that subsequently migrate to the lung and promote allergic airway inflammation. Tfh2 cell development depends on the expression of the transcription factor Bcl6, which functions as a transcriptional repressor that prevents Blimp1 expression and the acquisition of the Th2 effector program. The cytokines IL-2, TSLP, IL-33, and IL-10 promote Blimp1 expression and thus drive differentiation of Th2 effectors from tfh2 cells.

Figure 3

Mechanisms that favor Th2-biased immune responses at early ages. Infants and young children are at higher risk of developing Th2 cell allergic responses than adults. The lack of inhibitory signals and the intensification of triggering factors contribute to the increase in Th2-biased immunity and sensitization to allergens during early childhood. A malfunctioning GM-CSF-moDC axis conditions for LPS hyporesponsiveness during infancy, hindering the induction of T-bet expression on cDC2s and thus driving deficient IL-12 responses. Early dietary practices and exposure to environmental microorganism may shape the maturation of the infant microbiome into compositions that enhance the GM-CSF-moDC axis and protect against sensitization to airborne allergens. On the other hand, a hyperactive IL-33 axis operating in the lung during the early postnatal period increases IL-13 production by ILC2, which activates the migration and pro-Th2 function of cDC2s. Additionally, exposure to inhalable particulate pollutants can intensify this tendency.