PI3-Kinase-γ Has a Distinct and Essential Role in Lung-Specific Dendritic Cell Development

Nobs, Samuel Philip; Schneider, Christoph; Dietrich, Maren; Brocker, Thomas; Rolink, Antonius; Hirsch, Emilio

doi:10.1016/j.immuni.2015.09.006

Cited by 29 publications

(41 citation statements)

References 39 publications

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“…cDC1s – essential for preserving immune tolerance and mounting antiviral and antitumour responses 15 critically depend on the transcription factors Batf3, Irf8 and Id2 for their development 55 . Besides, additional factors have been identified that do not affect lymphoid tissue resident cDC1s homeostasis, but seem to have profound roles in the maintenance of peripheral tissue cDC1s, such as Csf2rb 25 , MycL 56 and PI3Kγ 57 . Here we add XBP1, a major transcription factor of the UPR to the growing list of regulators involved in the homeostasis of tissue-resident cDC1s.…”

Section: Discussionmentioning

confidence: 99%

Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival

et al. 2017

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Summary The IRE1/XBP1 signaling pathway is part of a cellular program that protects from endoplasmic reticulum (ER) stress, but also controls development and survival of immune cells. Loss of XBP1 in splenic type 1 conventional dendritic cells (cDC1s) results in phenotypic and functional alterations without affecting cell survival. However, in mucosal cDC1s, loss of XBP1 impaired survival in a tissue specific manner - while lung cDC1s die, intestinal cDC1s survive. This was not caused by differential activation of ER stress cell death regulators CHOP or JNK. Rather, cell fate was determined by a differential ability to shut down protein synthesis via a protective ATF4-dependent integrated stress response. In addition, regulated IRE1 dependent mRNA decay (RIDD) occurred mainly in intestinal cDC1s, and compound deficiency of IRE1 endonuclease led to cDC1 loss also in the intestine. Thus, mucosal DCs differentially mount ATF4 and IRE1 dependent adaptive mechanisms to survive in the face of ER stress.

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Section: Discussionmentioning

confidence: 99%

Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival

et al. 2017

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“…In this model inhibition of mTORC1 by rapamycin is able to reverse the defect conferred by Lamtor2 deletion. Recent evidence has implicated PI3Kγ upstream of mTORC 1 in the development of CD103 + DCs in the lungs (Nobs et al, 2015). …”

Section: Mtor In the Innate Immune Systemmentioning

confidence: 99%

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

2017

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Tissue-resident immune cells must balance survival in peripheral tissues with the capacity to respond rapidly upon infection or tissue damage, and in turn couple these responses with intrinsic metabolic control and conditions in the tissue microenvironment. The serine/threonine kinase mammalian/mechanistic target of rapamycin (mTOR) is a central integrator of extracellular and intracellular growth signals and cellular metabolism and plays important roles in both innate and adaptive immune responses. This review discusses the function of mTOR signaling in the differentiation and function of tissue-resident immune cells, with focus on the role of mTOR as a metabolic sensor and its impact on metabolic regulation in innate and adaptive immune cells. We also discuss the impact of metabolic constraints in tissues on immune homeostasis and disease, and how manipulating mTOR activity with drugs such as rapamycin can modulate immunity in these contexts.

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“…Dendritic cells (DCs) are sentinel immune cells that develop from hematopoietic progenitors into functionally distinct subsets, including two types of conventional DCs (cDCs), cDC1 and cDC2, and plasmacytoid dendritic cells (pDC) . Fms‐related tyrosine kinase 3 ligand (Flt3L) induces DC differentiation and activates nutrient‐sensitive signaling pathways, including phosphoinositide 3‐kinase (PI3K)/mammalian target of rapamycin . Emerging evidence implicates the metabolic state of hematopoietic cells as a determinant of cell fate .…”

Section: Introductionmentioning

confidence: 99%

Metabolic control of cell fate bifurcations in a hematopoietic progenitor population

et al. 2018

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Growth signals drive hematopoietic progenitor cells to proliferate and branch into divergent cell fates, but how unequal outcomes arise from a common progenitor is not fully understood. We used steady-state analysis of in vivo hematopoiesis and Fms-related tyrosine kinase 3 ligand (Flt3L)-induced in vitro differentiation of dendritic cells (DCs) to determine how growth signals regulate lineage bias. We found that Flt3L signaling induced anabolic activation and proliferation of DC progenitors, which was associated with DC differentiation. Perturbation of processes associated with quiescence and catabolism, including AMP-activated protein kinase signaling, fatty acid oxidation, or mitochondrial clearance increased development of cDC2 cells at the expense of cDC1 cells. Conversely, scavenging anabolism-associated reactive oxygen species skewed differentiation toward cDC1 cells. Sibling daughter cells of dividing DC progenitors exhibited unequal expression of the transcription factor interferon regulatory factor 8, which correlated with clonal divergence in FoxO3a signaling and population-level bifurcation of cell fate. We propose that unequal transmission of growth signals during cell division might support fate branches during proliferative expansion of progenitors.

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PI3-Kinase-γ Has a Distinct and Essential Role in Lung-Specific Dendritic Cell Development

Cited by 29 publications

References 39 publications

Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival

Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

Metabolic control of cell fate bifurcations in a hematopoietic progenitor population

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