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Allergic disorders are caused by a combination of hereditary and environmental factors. The hygiene hypothesis postulates that early-life microbial exposures impede the development of subsequent allergic disease. Recently developed "wildling" mice are genetically identical to standard laboratory specific pathogen-free (SPF) mice but are housed under seminatural conditions and have rich microbial exposures from birth. Thus, by comparing conventional SPF mice with wildlings, we can uncouple the impact of lifelong microbial exposures from genetic factors on the allergic immune response. We found that wildlings developed larger populations of antigen-experienced T cells than conventional SPF mice, which included interleukin-10-producing CD4 T cells specific for commensal Lactobacilli strains and allergy-promoting T helper 2 (T H 2) cells. In models of airway exposure to house dust mite (HDM), recombinant interleukin-33, or Alternaria alternata , wildlings developed strong allergic inflammation, characterized by eosinophil recruitment, goblet cell metaplasia, and antigen-specific immunoglobulin G1 (IgG1) and IgE responses. Wildlings developed robust de novo T H 2 cell responses to incoming allergens, whereas preexisting T H 2 cells could also be recruited into the allergic immune response in a cytokine-driven and TCR-independent fashion. Thus, wildling mice, which experience diverse and lifelong microbial exposures, were not protected from developing pathological allergic immune responses. Instead, wildlings mounted robust allergic responses to incoming allergens, shedding new light on the hygiene hypothesis.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a chronic inflammatory process often associated with comorbid asthma. In this study, we analyzed the transcriptomes of single T helper (T H ) cells from nasal polyps of patients with CRSwNP and validated these findings using multiparameter flow cytometry. Polyp tissue contained suppressive T regulatory (T reg ) cells, T H 2 cells, type 2 innate lymphoid cells, and three transcriptionally distinct subsets of cytotoxic CD4 + T cells (CD4 + CTL). GATA3 expression was a feature of polyp T reg cells, whereas T H 2 cells highly expressed TCN1 , CD200R , and HPGDS and were enriched for genes involved in lipid metabolism. Only a portion of polyp T H 2 cells expressed the prostaglandin D2 receptor CRTH2, whereas a subpopulation of CD109 + CRTH2 - T H 2 cells expressed mRNA for common inhibitor receptors including LAG3 and TIM3 and produced IL-10. Together, we resolved the complexity of T H cells in patients with CRSwNP, identifying several distinct clusters of CD4 + CTL and a population of CD109 + CRTH2 - T H 2 cells with putative regulatory potential., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Rhinovirus (RV) infections are associated with asthma exacerbations. MicroRNA-146a and microRNA-146b (miR-146a/b) are anti-inflammatory miRNAs that suppress signaling through the nuclear factor kappa B (NF-κB) pathway and inhibit pro-inflammatory chemokine production in primary human bronchial epithelial cells (HBECs). In the current study, we aimed to explore whether miR-146a/b could regulate cellular responses to RVs in HBECs and airways during RV-induced asthma exacerbation. We demonstrated that expression of miR-146a/b and pro-inflammatory chemokines was increased in HBECs and mouse airways during RV infection. However, transfection with cell-penetrating peptide (CPP)-miR-146a nanocomplexes before infection with RV significantly reduced the expression of the pro-inflammatory chemokines CCL5, IL-8 and CXCL1, increased interferon-λ production, and attenuated infection with the green fluorescent protein (GFP)-expressing RV-A16 in HBECs. Concordantly, compared to wild-type (wt) mice, Mir146a/b -/- mice exhibited more severe airway neutrophilia and increased T helper (Th)1 and Th17 cell infiltration in response to RV-A1b infection and a stronger Th17 response with a less prominent Th2 response in house dust mite extract (HDM)-induced allergic airway inflammation and RV-induced exacerbation models. Interestingly, intranasal administration of CPP-miR-146a nanocomplexes reduced HDM-induced allergic airway inflammation without a significant effect on the Th2/Th1/Th17 balance in wild-type mice. In conclusion, the overexpression of miR-146a has a strong anti-inflammatory effect on RV infection in HBECs and a mouse model of allergic airway inflammation, while a lack of miR-146a/b leads to attenuated type 2 cell responses in mouse models of allergic airway inflammation and RV-induced exacerbation of allergic airway inflammation. Furthermore, our data indicate that the application of CPP-miR-146a nanocomplexes has therapeutic potential for targeting airway inflammation., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Upon activation, naïve CD4 + T cells differentiate into a number of specialized T helper (Th) cell subsets. Th2 cells are central players in immunity to helminths and are implicated in mediating the inflammatory pathology associated with allergies. The differentiation of Th2 cells is dependent on transcription factors such as GATA3 and STAT6, which prime Th2 cells for the secretion of interleukin- (IL-) 4, IL-5, and IL-13. Several lines of work now suggest that differentiating Th2 cells in the lymph node are potent IL-4 cytokine producers, but do not become competent IL-5- and IL-13-producing cells until after receiving cues from non-lymphoid tissue. It is evident that Th2 cells that enter tissues undergo considerable changes in chromatin architecture and gene expression, and that over this time, the metabolic requirements of these cells change considerably. Herein, we discuss the metabolic requirements of Th2 cells during their early and late differentiation, focusing on the impact of glucose and lipid metabolism, mTOR activation, the nuclear receptor PPAR-γ and several metabolites., (Copyright © 2019 Stark, Tibbitt and Coquet.)

Naive CD4 + T cells differentiate into functionally diverse T helper (Th) cell subsets. Th2 cells play a pathogenic role in asthma, yet a clear picture of their transcriptional profile is lacking. We performed single-cell RNA sequencing (scRNA-seq) of T helper cells from lymph node, lung, and airways in the house dust mite (HDM) model of allergic airway disease. scRNA-seq resolved transcriptional profiles of naive CD4 + T, Th1, Th2, regulatory T (Treg) cells, and a CD4 + T cell population responsive to type I interferons. Th2 cells in the airways were enriched for transcription of many genes, including Cd200r1, Il6, Plac8, and Igfbp7, and their mRNA profile was supported by analysis of chromatin accessibility and flow cytometry. Pathways associated with lipid metabolism were enriched in Th2 cells, and experiments with inhibitors of key metabolic pathways supported roles for glucose and lipid metabolism. These findings provide insight into the differentiation of pathogenic Th2 cells in the context of allergy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Asthma is a T helper 2 (Th2)-cell-mediated disease; however, recent findings implicate Th17 and innate lymphoid cells also in regulating airway inflammation. Herein, we have demonstrated profound interleukin-21 (IL-21) production after house dust mite (HDM)-driven asthma by using T cell receptor (TCR) transgenic mice reactive to Dermatophagoides pteronyssinus 1 and an IL-21GFP reporter mouse. IL-21-producing cells in the mediastinal lymph node (mLN) bore characteristics of T follicular helper (Tfh) cells, whereas IL-21(+) cells in the lung did not express CXCR5 (a chemokine receptor expressed by Tfh cells) and were distinct from effector Th2 or Th17 cells. Il21r(-/-) mice developed reduced type 2 responses and the IL-21 receptor (IL-21R) enhanced Th2 cell function in a cell-intrinsic manner. Finally, administration of recombinant IL-21 and IL-25 synergistically promoted airway eosinophilia primarily via effects on CD4(+) lymphocytes. This highlights an important Th2-cell-amplifying function of IL-21-producing CD4(+) T cells in allergic airway inflammation., (Copyright © 2015 Elsevier Inc. All rights reserved.)