Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung

He, Kun; Hettinga, Angela; Kale, Sagar Laxman; Hu, Sanmei; Xie, Markus M.; Dent, Alexander L.; Ray, Anuradha; Poholek, Amanda C.

doi:10.1084/jem.20190742

Cited by 35 publications

(36 citation statements)

References 77 publications

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“…Similarly, the role of Blimp-1 in the immune system is highly context dependent and tissue specific. For example, it was recently shown that Blimp-1 is an unexpected positive regulator of Th2 responses in the lung, facilitated through an IL-10/STAT3 axis ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis

Beppu¹,

Mooli²,

Qu³

et al. 2021

JCI Insight

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Interleukin-10 (IL-10) is a critical cytokine used by immune cells to suppress inflammation. Paradoxically, immune cell–derived IL-10 can drive insulin resistance in obesity by suppressing adipocyte energy expenditure and thermogenesis. However, the source of IL-10 necessary for the suppression of adipocyte thermogenesis is unknown. We show here that CD4 + Foxp3 + regulatory T cells (Tregs) are a substantial source of IL-10 and that Treg-derived IL-10 can suppress adipocyte beiging. Unexpectedly, Treg-specific loss of IL-10 resulted in increased insulin sensitivity and reduced obesity in high-fat diet–fed male mice. Mechanistically, we determined that Treg-specific loss of the transcription factor Blimp-1, a driver of IL-10 expression by Tregs, phenocopied the Treg-specific IL-10–deficient mice. Loss of Blimp-1 expression in Tregs resulted in reduced ST2 + KLRG1 + , IL-10-secreting Tregs, particularly in the white adipose tissue. Blimp-1–deficient mice were protected from glucose intolerance, insulin resistance, and diet-induced obesity, through increased white adipose tissue browning. Taken together, our data show that Blimp-1–regulated IL-10 secretion by Tregs represses white adipose tissue beiging to maintain adipose tissue homeostasis.

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Section: Discussionmentioning

confidence: 99%

Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis

Beppu¹,

Mooli²,

Qu³

et al. 2021

JCI Insight

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“…Consistently, Uwadiae et al 100 discovered that the administration of anti‐ICOS ligand antibody specifically disrupted T FH cell responses, accompanied by reduced lung inflammation and airway hyper‐responsiveness in a mouse asthma model induced by HDM. In a similar model, He et al 101 reported that the deletion of Blimp‐1 upregulated Bcl‐6 expression in CD4 + T cells, leading to the suppression of Gata3 expression and T H 2 cell differentiation. Their results suggest distinct mechanisms underpinning T FH and T H 2 cell differentiation in response to allergens and Blimp‐1 as a rheostat oppositely determining T FH vs T H 2 fate commitment in the murine model of allergic asthma.…”

Section: Tfh and Tfr Cells In Allergic Diseasesmentioning

confidence: 95%

Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy

Yao

Chen

et al. 2020

Allergy

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Allergic diseases are characterized by overactive type 2 immune responses to allergens and immunoglobulin E (IgE)‐mediated hypersensitivity. Emerging evidence suggests that follicular helper T (TFH) cells, rather than type 2 T‐helper (TH2) cells, play a crucial role in controlling IgE production. However, follicular regulatory T (TFR) cells, a specialized subset of regulatory T (TREG) cells resident in B‐cell follicles, restricts TFH cell‐mediated help in extrafollicular antibody production, germinal center (GC) formation, immunoglobulin affinity maturation, and long‐lived, high‐affinity plasma and memory B‐cell differentiation. In mouse models of allergic asthma and food allergy, CXCR5+ TFH cells, not CXCR5− conventional TH2 cells, are needed to support IgE production, otherwise exacerbated by CXCR5+ TFR cell deletion. Upregulation of TFH cell activities, including a skewing toward type 2 TFH (TFH2) and IL‐13 producing TFH (TFH13) phenotypes, and defects in TFR cells have been identified in patients with allergic diseases. Allergen immunotherapy (AIT) reinstates the balance between TFH and TFR cells in patients with allergic diseases, resulting in clinical benefits. Collectively, further understanding of TFH and TFR cells and their role in the immunopathogenesis of allergic diseases creates opportunities to develop novel therapeutic approaches.

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“…As a result of their efforts, they not only confirmed GATA3, Stat6, Batf, PPARγ, and IRF4 as key transcription factors that are involved in Th2 cell differentiation and activation but also revealed Bhlhe40, Bcl11b, and Xbp1 as transcription factors that are involved in Th2 cell activation. While more factors that are involved in regulating Th1/Th2 differentiation and functions are still being discovered, including the p53 family protein p73, which affects Th1 cell differentiation 63 , and Blimp-1, which regulates GATA3 expression and thus Th2 cell differentiation 64 , the combination of novel genome-level technologies such as CRISPR knockout with high-throughput sequencing will hopefully reveal more non-lineage-related transcription factors in modulating CD4 T cell differentiation.…”

Section: New Roles For Known Transcription Factors In Regulating the mentioning

confidence: 99%

Recent advances in understanding the Th1/Th2 effector choice

Butcher

Zhu

2021

Fac Rev

103

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For over 35 years since Mosmann and Coffman proposed the seminal “type 1 T helper (Th1)/type 2 T helper (Th2)” hypothesis in 1986, the immunological community has appreciated that naïve CD4 T cells need to make important decisions upon their activation, namely to differentiate towards a Th1, Th2, Th17 (interleukin-17-producing T helper), follicular T helper (Tfh), or regulatory T cell (Treg) fate to orchestrate a variety of adaptive immune responses. The major molecular underpinnings of the Th1/Th2 effector fate choice had been initially characterized using excellent reductionist in vitro culture systems, through which the transcription factors T-bet and GATA3 were identified as the master regulators for the differentiation of Th1 and Th2 cells, respectively. However, Th1/Th2 cell differentiation and their cellular heterogeneity are usually determined by a combinatorial expression of multiple transcription factors, particularly in vivo , where dendritic cell (DC) and innate lymphoid cell (ILC) subsets can also influence T helper lineage choices. In addition, inflammatory cytokines that are capable of inducing Th17 cell differentiation are also found to be induced during typical Th1- or Th2-related immune responses, resulting in an alternative differentiation pathway, transiting from a Th17 cell phenotype towards Th1 or Th2 cells. In this review, we will discuss the recent advances in the field, focusing on some new players in the transcriptional network, contributions of DCs and ILCs, and alternative differentiation pathways towards understanding the Th1/Th2 effector choice in vivo .

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Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung

Cited by 35 publications

References 77 publications

Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis

Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis

Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy

Recent advances in understanding the Th1/Th2 effector choice

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