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.
The Role of PPAR-γ in Allergic Disease Stark, Julian M.; Coquet, Jonathan M.; Tibbitt, Christopher A.
Current allergy and asthma reports,
11/2021, Volume:
21, Issue:
11
Journal Article
Peer reviewed
Open access
Purpose of Review
The incidence of allergic diseases such as asthma, rhinitis and atopic dermatitis has risen at an alarming rate over the last century. Thus, there is a clear need to understand the ...critical factors that drive such pathologic immune responses. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that has emerged as an important regulator of multiple cell types involved in the inflammatory response to allergens; from airway epithelial cells to T Helper (TH) cells.
Recent Findings
Initial studies suggested that agonists of PPAR-γ could be employed to temper allergic inflammation, suppressing pro-inflammatory gene expression programs in epithelial cells. Several lines of work now suggest that PPAR-γ plays an essential in promoting ‘type 2’ immune responses that are typically associated with allergic disease. PPAR-γ has been found to promote the functions of TH2 cells, type 2 innate lymphoid cells, M2 macrophages and dendritic cells, regulating lipid metabolism and directly inducing effector gene expression. Moreover, preclinical models of allergy in gene-targeted mice have increasingly implicated PPAR-γ in driving allergic inflammation.
Summary
Herein, we highlight the contrasting roles of PPAR-γ in allergic inflammation and hypothesize that the availability of environmental ligands for PPAR-γ may be at the heart of the rise in allergic diseases worldwide.
Allergy to dogs affects around 10% of the population in developed countries. Immune therapy of allergic patients with dog allergen extracts has shown limited therapeutic benefit.
We established a ...mouse model of dog allergy by repeatedly administering dog dander and epithelium extracts via the intranasal route. We also assessed the efficacy of a recombinant multimeric protein containing Can f 1, f 2, f 4 and f 6 in preventing inflammatory responses to dog extracts.
Repeated inhalation of dog extracts induced infiltration of the airways by T
2 cells, eosinophils and goblet cells, reminiscent of the house dust mite (HDM) model of asthma. Dog extracts also induced robust airway hyperresponsiveness and promoted T
17 cell responses, which was associated with a high neutrophilic infiltration of the airways. scRNA-Seq analysis of T helper cells in the airways pinpointed a unique gene signature for T
17 cells. Analysis of T-cell receptors depicted a high frequency of clones that were shared between T
17, T
2 and suppressive Treg cells, indicative of a common differentiation trajectory for these subsets. Importantly, sublingual administration of multimeric Can f 1-2-4-6 protein prior to sensitization reduced airway hyperresponsiveness and type 2-mediated inflammation in this model.
Dog allergen extracts induce robust T
2 and T
17 cell-mediated responses in mice. Recombinant Can f 1-2-4-6 can induce tolerance to complex dog allergen extracts.
Objective- Dyslipidemia is a component of the metabolic syndrome, an established risk factor for atherosclerotic cardiovascular disease, and is also observed in various autoimmune and chronic ...inflammatory conditions. However, there are limited opportunities to study the impact of acquired dyslipidemia on cardiovascular and immune pathology. Approach and Results- We designed a model system that allows for the conversion to a state of acute hyperlipidemia in adult life, so that the consequences of such a transition could be observed, through conditionally deleting APOE (apolipoprotein E) in the adult mouse. The transition to hypercholesterolemia was accompanied by adaptive immune responses, including the expansion of T lymphocyte helper cell 1, T follicular helper cell, and T regulatory subsets and the formation of germinal centers. Unlike steady-state Apoe
mice, abrupt loss of APOE induced rapid production of antibodies recognizing rheumatoid disease autoantigens. Genetic ablation of the germinal center reduced both autoimmunity and atherosclerosis, indicating that the immune response that follows loss of APOE is independent of atherosclerosis but nevertheless promotes plaque development. Conclusions- Our findings suggest that immune activation in response to hyperlipidemia could contribute to a wide range of inflammatory autoimmune diseases, including atherosclerosis.
Background
Allergy to dogs affects around 10% of the population in developed countries. Immune therapy of allergic patients with dog allergen extracts has shown limited therapeutic benefit.
Methods
...We established a mouse model of dog allergy by repeatedly administering dog dander and epithelium extracts via the intranasal route. We also assessed the efficacy of a recombinant multimeric protein containing Can f 1, f 2, f 4 and f 6 in preventing inflammatory responses to dog extracts.
Results
Repeated inhalation of dog extracts induced infiltration of the airways by TH2 cells, eosinophils and goblet cells, reminiscent of the house dust mite (HDM) model of asthma. Dog extracts also induced robust airway hyperresponsiveness and promoted TH17 cell responses, which was associated with a high neutrophilic infiltration of the airways. scRNA‐Seq analysis of T helper cells in the airways pinpointed a unique gene signature for TH17 cells. Analysis of T‐cell receptors depicted a high frequency of clones that were shared between TH17, TH2 and suppressive Treg cells, indicative of a common differentiation trajectory for these subsets. Importantly, sublingual administration of multimeric Can f 1‐2‐4‐6 protein prior to sensitization reduced airway hyperresponsiveness and type 2‐mediated inflammation in this model.
Conclusion
Dog allergen extracts induce robust TH2 and TH17 cell‐mediated responses in mice. Recombinant Can f 1‐2‐4‐6 can induce tolerance to complex dog allergen extracts.
Intranasal administration of dog allergen extracts induces airway hyperresponsiveness and robust TH17 cell‐driven neutrophilia. Single cell RNA‐Sequencing pinpoints distinct gene expression signatures between canonical TH cell subsets and shows considerable clonal overlap between TH2, TH17, Treg and TFH cells. A recombinant multimer of lipocalin allergens (Can f 1‐2‐4‐6) reduces TH2 cell responses and airway hyperresponsiveness when administered prophylactically.Abbreviations: AHR, airway hyperresponsiveness; CCR6, C‐C motif chemokine receptor 6; CXCR5, C‐X‐C chemokine receptor 5; EOS, eosinophil; IL, interleukin; NEU, neutrophil; Tfh, follicular T helper cell; Treg, regulatory T helper cell
Introduction
Innate lymphoid cells (ILCs) can provide early cytokine help against a variety of pathogens in the lungs and gastrointestinal tract. Type 2 ILC (ILC2) are comparable to T helper 2 cells ...found in the adaptive immune system, which secrete cytokines such as interleukin 5 (IL‐5) and IL‐13 and have been found to play roles in host defense against helminth infections and in allergic responses. Recent studies have identified that programmed cell death protein 1 (PD‐1) and peroxisome proliferator activated receptor‐γ (PPAR‐γ) are highly expressed by ILC2. We examined whether PD‐1 plays a role in ILC2 function and whether there was any connection between PD‐1 and PPAR‐γ
Methods
To ensure that only innate immune cells were present, ILC2 cells were examined from RAG1−/− and PD‐1−/−xRAG1−/− mice under steady‐state or following inoculation with IL‐33. We also tested ILC2 generated from bone marrow of RAG1−/− and PD‐1−/−xRAG1−/− mice for their production of cytokines. These in vitro‐derived ILC2 were also exposed to agonist and antagonist of PPAR‐γ.
Results
We found that ILC2 from PD‐1−/−xRAG1−/− mice had reduced frequencies of IL‐5 and IL‐13 producing cells both in vitro upon IL‐33 stimulation and in vivo following intraperitoneal administration of IL‐33 when compared with ILC2 from RAG1−/− mice. However, by adding IL‐2, IL‐25, and thymic stromal lymphopoietin to the in vitro cultures, the frequency of IL‐5 and IL‐13 expressing ILC2 from PD‐1−/−xRAG1−/− mice became similar to the frequency observed for ILC2 from RAG1−/− mice. In addition, PPAR‐γ agonists and antagonists were found to increase and decrease PD‐1 expression on ILC2 respectively.
Conclusions
These findings illustrate that chronic loss of PD‐1 plays a role in ILC2 function and PD‐1 expression can be modulated by PPAR‐γ.
Intestinal helminth parasites can alter immune responses to vaccines, other infections, allergens and autoantigens, implying effects on host immune responses in distal barrier tissues. We herein show ...that the skin of C57BL/6 mice infected with the strictly intestinal nematode Heligmosomoides polygyrus contain higher numbers of CD4
T cells compared to the skin of uninfected controls. Accumulated CD4
T cells were H. polygyrus-specific T
2 cells that skewed the skin CD4
T cell composition towards a higher T
2/T
1 ratio which persisted after worm expulsion. Accumulation of T
2 cells in the skin was associated with increased expression of the skin-homing chemokine receptors CCR4 and CCR10 on CD4
T cells in the blood and mesenteric lymph nodes draining the infected intestine and was abolished by FTY720 treatment during infection, indicating gut-to-skin trafficking of cells. Remarkably, skin T
2 accumulation was associated with impaired capacity to initiate IFN-γ recall responses and develop skin-resident memory cells to mycobacterial antigens, both during infection and months after deworming therapy. In conclusion, we show that infection by a strictly intestinal helminth has long-term effects on immune cell composition and local immune responses to unrelated antigens in the skin, revealing a novel process for T cell colonisation and worm-mediated immunosuppression in this organ.
Mice deficient in central components of classical NF-κB signaling have low levels of circulating natural IgM antibodies and fail to respond to immunization with T-independent type 2 (TI-2) antigens. ...A plausible explanation for these defects is the severely reduced numbers of B-1 and marginal zone B (MZB) cells in such mice. By using an ethyl-N-nitrosourea mutagenesis screen, we identified a role for the atypical IκB protein IκBNS in humoral immunity. IκBNS-deficient mice lack B-1 cells and have severely reduced numbers of MZB cells, and thus resemble several other strains with defects in classical NF-κB signaling. We analyzed mice heterozygous for the identified IκBNS mutation and demonstrate that these mice have an intermediary phenotype in terms of levels of circulating IgM antibodies and responses to TI-2 antigens. However, in contrast to mice that are homozygous for the IκBNS mutation, the heterozygous mice had normal frequencies of B-1 and MZB cells. These results suggest that there is a requirement for IκBNS expression from two functional alleles for maintaining normal levels of circulating natural IgM antibodies and responses to TI-2 antigens.
Well-ordered soluble HIV-1 envelope glycoprotein (Env) spike mimetics such as Native Flexibly Linked (NFL) trimers display high homogeneity, desired antigenicity, and high
stability compared to ...previous generation soluble HIV-1 Env trimers. Glutaraldehyde (GLA) cross-linking was shown to further increase the thermostability of clade C 16055 NFL trimers and enhance the induction of tier 2 autologous neutralizing antibodies in guinea pigs. Here, we investigated if GLA fixation affected other aspects of the Env-specific immune response by performing a comparative immunogenicity study in C57BL/6 mice with non-fixed and GLA-fixed 16055 NFL trimers administered in AbISCO-100 adjuvant. We detected lower Env-specific binding antibody titers and increased skewing toward Th2 responses in mice immunized with GLA-fixed trimers compared to mice immunized with unfixed trimers, as shown by a higher Env-specific IgG1:IgG2b antibody subclass ratio. These results suggest that the presence of GLA adducts on Env influences the quality of the induced antibody response.
Impaired classical NF‐κB pathway signaling causes reduced antibody responses to T‐independent (TI) antigens. We investigated the potential reasons for defective TI responses in mice lacking the ...atypical inhibitory kappa B (IκB) protein of the NF‐κB pathway, IκBNS. Analyses of the plasma cell compartment in vitro and in vivo after challenge with lipopolysaccharide (LPS) showed significant decreases in the frequencies of plasma cells in the absence of IκBNS. In vitro activation of B cells via the B cell receptor or via Toll‐like receptor 4 revealed that early activation events were unaffected in IκBNS‐deficient B cells, while proliferation was reduced compared to in similarly stimulated wildtype (wt) B cells. IκBNS‐deficient B cells also displayed impaired upregulation of the transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), which is essential for TI responses, and decreased sensitivity to TACI ligands upon stimulation. Furthermore, IκBNS‐deficient B cells, in contrast to wt B cells, displayed altered expression of IRF4, Blimp‐1 and Pax5 upon LPS‐induced differentiation, indicating impaired transcriptional regulation of plasma cell generation.
This study identified alterations in B cell activation and plasma cell differentiation as underlying reasons for the impaired humoral responses against T‐independent (TI) antigens associated with IκBNS deficiency. In the absence of IκBNS, B cells exhibited reduced proliferative capacity, a loss of TACI‐mediated antibody production, and altered expression of the transcription factors Pax5, IRF4 and Blimp‐1, and fail to generate plasma cells. These findings indicate that TACI function and plasma cell differentiation are regulated by IκBNS, and may help explain mechanisms for impaired TI responses associated with defects in components of the NF‐κB signaling pathway.
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