scholarly journals Alternatively activated macrophage-derived RELM-α is a negative regulator of type 2 inflammation in the lung

2009 ◽  
Vol 206 (4) ◽  
pp. 937-952 ◽  
Author(s):  
Meera G. Nair ◽  
Yurong Du ◽  
Jacqueline G. Perrigoue ◽  
Colby Zaph ◽  
Justin J. Taylor ◽  
...  
Keyword(s):  
T Cell ◽  
Lung Inflammation ◽  
Negative Regulator ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Th2 Cytokine ◽  
Arginase 1 ◽  
Alternatively Activated

Differentiation and recruitment of alternatively activated macrophages (AAMacs) are hallmarks of several inflammatory conditions associated with infection, allergy, diabetes, and cancer. AAMacs are defined by the expression of Arginase 1, chitinase-like molecules, and resistin-like molecule (RELM) α/FIZZ1; however, the influence of these molecules on the development, progression, or resolution of inflammatory diseases is unknown. We describe the generation of RELM-α–deficient (Retnla−/−) mice and use a model of T helper type 2 (Th2) cytokine-dependent lung inflammation to identify an immunoregulatory role for RELM-α. After challenge with Schistosoma mansoni (Sm) eggs, Retnla−/− mice developed exacerbated lung inflammation compared with their wild-type counterparts, characterized by excessive pulmonary vascularization, increased size of egg-induced granulomas, and elevated fibrosis. Associated with increased disease severity, Sm egg–challenged Retnla−/− mice exhibited elevated expression of pathogen-specific CD4+ T cell–derived Th2 cytokines. Consistent with immunoregulatory properties, recombinant RELM-α could bind to macrophages and effector CD4+ Th2 cells and inhibited Th2 cytokine production in a Bruton's tyrosine kinase–dependent manner. Additionally, Retnla−/− AAMacs promoted exaggerated antigen-specific Th2 cell differentiation. Collectively, these data identify a previously unrecognized role for AAMac-derived RELM-α in limiting the pathogenesis of Th2 cytokine-mediated pulmonary inflammation, in part through the regulation of CD4+ T cell responses.

scholarly journals IL-31–IL-31R interactions negatively regulate type 2 inflammation in the lung

2007 ◽  
Vol 204 (3) ◽  
pp. 481-487 ◽  
Author(s):  
Jacqueline G. Perrigoue ◽  
Ji Li ◽  
Colby Zaph ◽  
Michael Goldschmidt ◽  
Phillip Scott ◽  
...  
Keyword(s):  
T Cell ◽  
Granulomatous Inflammation ◽  
Oncostatin M ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
Regulatory Function ◽  
Negative Regulatory Pathway ◽  
Type 2 Inflammation

Interleukin (IL) 31Rα (glycoprotein 130–like monocyte receptor and glycoprotein 130–like receptor) heterodimerizes with oncostatin M receptor β to bind IL-31, a cytokine expressed preferentially by CD4+ T helper type 2 (Th2) cells. However, the functions of IL-31–IL-31R signaling in immune regulation remain unknown. Here, we identify a novel role for IL-31R in limiting type 2 inflammation in the lung. After intravenous injection of Schistosoma mansoni eggs, IL-31Rα−/− mice developed severe pulmonary inflammation, characterized by an increase in the area of granulomatous inflammation, increased numbers of resistin-like molecule α+ cells, and enhanced collagen deposition compared to WT counterparts. In vitro, macrophages generated from IL-31Rα−/− mice promoted enhanced ovalbumin-specific CD4+ T cell proliferation and purified naive CD4+ T cells from IL-31Rα−/− mice exhibited enhanced proliferation and expression of Th2 cytokines, identifying a T cell– and macrophage-intrinsic regulatory function for IL-31R signaling. In contrast, the generation of CD4+ T cell–mediated Th1 responses were normal in IL-31Rα−/− mice, suggesting that the regulatory role of IL-31R signaling is limited to type 2 responses. Together, these data implicate IL-31R signaling as a novel negative regulatory pathway that specifically limits type 2 inflammation.

scholarly journals Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner

2020 ◽  
Vol 21 (18) ◽  
pp. 6965 ◽  
Author(s):  
Tiago Carvalheiro ◽  
Carlos Rafael-Vidal ◽  
Beatriz Malvar-Fernandez ◽  
Ana P. Lopes ◽  
Jose M. Pego-Reigosa ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Neutralizing Antibody ◽  
Negative Regulator ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Th17 Differentiation

Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4+ T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naïve Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORγt in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4+ T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4+ T cell-mediated diseases.

scholarly journals TIM-1 and TIM-3 enhancement of Th2 cytokine production by mast cells

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2565-2568 ◽  
Author(s):  
Susumu Nakae ◽  
Motoyasu Iikura ◽  
Hajime Suto ◽  
Hisaya Akiba ◽  
Dale T. Umetsu ◽  
...  
Keyword(s):  
T Cell ◽  
Mast Cells ◽  
Immune Responses ◽  
Cytokine Production ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
T Helper ◽  
Th2 Cytokine ◽  
Peritoneal Mast Cells

Members of the T-cell immunoglobulin– and mucin-domain–containing molecule (TIM) family have roles in T-cell–mediated immune responses. TIM-1 and TIM-2 are predominantly expressed on T helper type 2 (Th2) cells, whereas TIM-3 is preferentially expressed on Th1 and Th17 cells. We found that TIM-1 and TIM-3, but neither TIM-2 nor TIM-4, were constitutively expressed on mouse peritoneal mast cells and bone marrow–derived cultured mast cells (BMCMCs). After IgE + Ag stimulation, TIM-1 expression was down-regulated on BMCMCs, whereas TIM-3 expression was up-regulated. We also found that recombinant mouse TIM-4 (rmTIM-4), which is a ligand for TIM-1, as well as an anti–TIM-3 polyclonal Ab, can promote interleukin-4 (IL-4), IL-6, and IL-13 production without enhancing degranulation in BMCMCs stimulated with IgE + Ag. Moreover, the anti–TIM-3 Ab, but neither anti–TIM-1 Ab nor rmTIM-4, suppressed mast-cell apoptosis. These observations suggest that TIM-1 and TIM-3 may be able to influence T-cell–mediated immune responses in part through effects on mast cells.

scholarly journals Miquelianin Inhibits Allergic Responses in Mice by Suppressing CD4+ T Cell Proliferation

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1120
Author(s):  
Dae Woon Choi ◽  
Sun Young Jung ◽  
Gun-Dong Kim ◽  
So-Young Lee ◽  
Hee Soon Shin
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Mouse Model ◽  
Immune Responses ◽  
Reactive Oxygen Species Generation ◽  
Allergic Diseases ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
T Cell Proliferation ◽  
Heme Oxygenase 1

Allergic diseases, including atopic dermatitis (AD), induce type 2 helper T (Th2) cell-dominant immune responses. Miquelianin (quercetin 3-O-glucuronide, MQL) is an active compound in Rosae multiflorae fructus extract with anti-allergic properties. Here, we investigate the anti-allergic effects of MQL in an ovalbumin (OVA)-induced Th2-dominant mouse model and the associated mechanisms. Oral MQL suppressed cytokine and IL-2 production and proliferation of Th2 cells and upregulated heme oxygenase-1 (HO-1) in splenocytes. Ex vivo MQL suppressed Th1- and Th2-related immune responses by inhibiting CD4+ T cell proliferation, and upregulated HO-1 in CD4+ T cells by activating C-Raf–ERK1/2–Nrf2 pathway via induction of reactive oxygen species generation. In a trimellitic anhydride-induced AD-like mouse model, both topical and oral MQL ameliorated AD symptoms by suppressing Th2 immune responses. Our results suggest that MQL is a potential therapeutic agent for CD4+ T cell-mediated diseases, including allergic diseases.

CD4+ T-cell activation of bone marrow causes bone fragility and insulin resistance in type 2 diabetes

Bone ◽  
2021 ◽  
pp. 116292
Author(s):  
S.E. Cifuentes-Mendiola ◽  
D.L. Solis-Suarez ◽  
A. Martínez-Dávalos ◽  
M. Godínez-Victoria ◽  
A.L. García-Hernández
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Bone Marrow ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bone Fragility ◽  
Cd4 T Cell

scholarly journals The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Masahiro Kiuchi ◽  
Atsushi Onodera ◽  
Kota Kokubo ◽  
Tomomi Ichikawa ◽  
Yuki Morimoto ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Allergic Airway Inflammation ◽  
T Cell Differentiation ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
Th2 Differentiation ◽  
Later Phase ◽  
Th1 And Th2

Different dynamics of gene expression are observed during cell differentiation. In T cells, genes that are turned on early or turned off and stay off have been thoroughly studied. However, genes that are initially turned off but then turned on again after stimulation has ceased have not been defined; they are obviously important, especially in the context of acute versus chronic inflammation. Using the Th1/Th2 differentiation paradigm, we found that the Cxxc1 subunit of the Trithorax complex directs transcription of genes initially down-regulated by TCR stimulation but up-regulated again in a later phase. The late up-regulation of these genes was impaired either by prolonged TCR stimulation or Cxxc1 deficiency, which led to decreased expression of Trib3 and Klf2 in Th1 and Th2 cells, respectively. Loss of Cxxc1 resulted in enhanced pathogenicity in allergic airway inflammation in vivo. Thus, Cxxc1 plays essential roles in the establishment of a proper CD4+ T cell immune system via epigenetic control of a specific set of genes.

scholarly journals F4/80+Alternatively Activated Macrophages Control CD4+T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

2006 ◽  
Vol 176 (11) ◽  
pp. 6918-6927 ◽  
Author(s):  
Matthew D. Taylor ◽  
Anjanette Harris ◽  
Meera G. Nair ◽  
Rick M. Maizels ◽  
Judith E. Allen
Keyword(s):  
T Cell ◽  
Cd4 T Cell ◽  
Activated Macrophages ◽  
Filarial Infection ◽  
Alternatively Activated Macrophages ◽  
Alternatively Activated

The potential impact of CD4+ T cell activation and enhanced Th1/Th2 cytokine ratio on HIV-1 secretion in the lungs of individuals with advanced AIDS and active pulmonary infection

2011 ◽  
Vol 139 (2) ◽  
pp. 142-154 ◽  
Author(s):  
Pierre-Alain Rubbo ◽  
Edouard Tuaillon ◽  
Karine Bolloré ◽  
Vincent Foulongne ◽  
Arnaud Bourdin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Pulmonary Infection ◽  
Cd4 T Cell ◽  
Th2 Cytokine ◽  
Potential Impact ◽  
Hiv 1
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