scholarly journals BACH2 drives quiescence and maintenance of resting Treg cells to promote homeostasis and cancer immunosuppression

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Francis M. Grant ◽  
Jie Yang ◽  
Rabab Nasrallah ◽  
James Clarke ◽  
Firas Sadiyah ◽  
...  
Keyword(s):  
Chronic Exposure ◽  
Treg Cells ◽  
Lineage Commitment ◽  
Immune Homeostasis ◽  
Lineage Specification ◽  
Cell Quiescence ◽  
And Function ◽  
Term Maintenance ◽  
Cancer Immunosuppression

Regulatory T (Treg) cell populations are composed of functionally quiescent resting Treg (rTreg) cells which differentiate into activated Treg (aTreg) cells upon antigen stimulation. How rTreg cells remain quiescent despite chronic exposure to cognate self- and foreign antigens is unclear. The transcription factor BACH2 is critical for early Treg lineage specification, but its function following lineage commitment is unresolved. Here, we show that BACH2 is repurposed following Treg lineage commitment and promotes the quiescence and long-term maintenance of rTreg cells. Bach2 is highly expressed in rTreg cells but is down-regulated in aTreg cells and during inflammation. In rTreg cells, BACH2 binds to enhancers of genes involved in aTreg differentiation and represses their TCR-driven induction by competing with AP-1 factors for DNA binding. This function promotes rTreg cell quiescence and long-term maintenance and is required for immune homeostasis and durable immunosuppression in cancer. Thus, BACH2 supports a “division of labor” between quiescent rTreg cells and their activated progeny in Treg maintenance and function, respectively.

scholarly journals Treg cells maintain selective access to IL-2 and immune homeostasis despite substantially reduced CD25 function

2019 ◽  
Author(s):  
Erika T. Hayes ◽  
Cassidy E. Hagan ◽  
Daniel J. Campbell
Keyword(s):  
Patient Outcomes ◽  
Interleukin 2 ◽  
Treg Cells ◽  
Immune Homeostasis ◽  
Cd25 Expression ◽  
And Function ◽  
Precise Role ◽  
Selective Access

AbstractInterleukin-2 (IL-2) is a critical regulator of immune homeostasis through its impact on both regulatory T (Treg) and effector T (Teff) cells. However, the precise role of IL-2 in the maintenance and function of Treg cells in the adult peripheral immune system remains unclear. Here, we report that neutralization of IL-2 abrogated all IL-2 receptor signaling in Treg cells, resulting in rapid dendritic cell (DC) activation and subsequent Teff cell proliferation. By contrast, despite substantially reduced IL-2 sensitivity, Treg cells maintained selective IL-2 signaling and prevented immune dysregulation following treatment with the inhibitory anti-CD25 antibody PC61, even when CD25hi Treg cells were depleted. Thus, despite severely curtailed CD25 expression and function, Treg cells retain selective access to IL-2 that supports their anti-inflammatory functions in vivo. Antibody-mediated targeting of CD25 is being actively pursued for treatment of autoimmune disease and preventing allograft rejection, and our findings help inform therapeutic manipulation and design for optimal patient outcomes.

Impaired long-term maintenance and function of Bordetella pertussis specific B cell memory

Vaccine ◽  
2010 ◽  
Vol 28 (40) ◽  
pp. 6637-6646 ◽  
Author(s):  
Rachel M. Stenger ◽  
Mieke Smits ◽  
Betsy Kuipers ◽  
Jacqueline van Gaans-van den Brink ◽  
Martien Poelen ◽  
...  
Keyword(s):  
B Cell ◽  
Bordetella Pertussis ◽  
Cell Memory ◽  
B Cell Memory ◽  
And Function ◽  
Term Maintenance

scholarly journals Physiology and function of PNS axons rely on glycolic metabolism in myelinating Schwann cells

2020 ◽  
Author(s):  
Marie Deck ◽  
Gerben Van Hameren ◽  
Graham Campbell ◽  
Nathalie Bernard-Marissal ◽  
Jérôme Devaux ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Motor Neurons ◽  
Warburg Effect ◽  
Mutant Mice ◽  
Axon Terminals ◽  
And Function ◽  
Term Maintenance ◽  
The Warburg Effect

SummaryWhether glial cells use a particular metabolism to support axonal metabolism and function remains controversial. We show here that the deletion of PKM2, an enzyme essential for the Warburg effect, in mature myelinating Schwann cells (mSC) leads to a deficit of lactate in these cells and in peripheral nerves, and to motor defects despite no alteration of the myelin sheath. When electrically stimulated, peripheral nerve axons of mSC-PKM2 mutant mice failed to maintain lactate homeostasis, resulting in an impaired production of mitochondrial ATP. Action potential propagation was not changed but axonal mitochondria transport was altered, muscle axon terminals retracted and motor neurons showed cellular stress. Further reducing lactate availability through dichloroacetate treatment definitely aggravated axonal malfunction in mutant mice. Thus, cancer-like Warburg effect is essential in mSC for the long-term maintenance of peripheral nerve axons physiology and function.One Sentence SummaryLactate-dependent axons rely on Warburg effect in Schwann cells.

Disruption of the Osteoblast Niche by G-CSF Induces Hematopoietic Stem Cell Quiescence and Loss of Long-Term Repopulating Activity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2217-2217
Author(s):  
Priya K. Gopalan ◽  
Matthew J. Christopher ◽  
Daniel C. Link
Keyword(s):  
Bone Marrow ◽  
Molecular Mechanisms ◽  
Bone Marrow Cells ◽  
Hematopoietic Stem ◽  
Rna Profiling ◽  
Stem Cell Quiescence ◽  
Cd34 Cells ◽  
Cell Quiescence ◽  
And Function

Abstract There is evidence that hematopoietic stem cells (HSC) are physically localized to specialized areas in the bone marrow termed the vascular and osteoblast niches. It is not clear if there are differences in the capacity of these niches to support HSC function. We and others previously showed that G-CSF treatment suppresses both osteoblast number and function, effectively eliminating the osteoblast niche. In contrast, G-CSF treatment has no apparent effect on the microvasculature in the bone marrow, suggesting that the vascular niche is intact. In this study, we utilized this system to assess the capacity of each niche to support HSC function. We previously reported that the competitive repopulation capacity of bone marrow isolated from G-CSF treated mice is markedly reduced. This is not due to a simple loss of HSC in the bone marrow, as the number of HSC, phenotypically defined as lineage-CD41-CD48-CD150+ (SLAM) or lineage-Kit+Sca+CD34- cells, was comparable to control mice. Moreover, the long-term repopulating activity of sorted SLAM cells from G-CSF treated mice was reduced. This repopulating defect is not secondary to impaired homing to the bone marrow, as direct intrafemoral injection of G-CSF treated bone marrow cells failed to rescue the engraftment defect. Since G-CSF is able to stimulate HSC proliferation, we predicted that the defect in repopulating activity might be secondary to loss of HSC quiescence. Contrary to our prediction, the percentage of quiescent HSC in the bone marrow was actually increased in G-CSF treated mice. Whereas 28.0 ± 3.4% of control SLAM cells were labeled after treatment with BrdU for 48 hours, only 7.5 ± 0.8% of SLAM cells isolated from G-CSF mice were labeled (p < 0.008). Moreover, the percentage of SLAM cells in G0, as determined by Hoechst and pyronin staining, was increased in G-CSF treated mice (80.3 ± 5.0% versus 65.5 ± 6.8% in untreated mice, p=0.104). To elucidate the molecular mechanisms by which disruption of the osteoblast niche leads to a loss of HSC activity, we performed RNA profiling experiments on SLAM cells sorted from G-CSF or saline-treated mice. Consistent with the quiescent phenotype, a significant increase in the expression of the cell cycle inhibitor, Cdkn1a (p21waf1), was observed in G-CSF treated SLAM cells. Collectively, these data show that the osteoblast and vascular niches are not functionally redundant and suggest that it is the osteoblast niche that is key to maintaining long-term repopulating activity of HSC.

Efficacious long-term maintenance therapy with pantoprazole (PAN) in patients with Zollinger-Ellison syndrome

2001 ◽  
Vol 120 (5) ◽  
pp. A613-A613
Author(s):  
P BORNMAN ◽  
K RADEBOLD ◽  
H DEBAERE ◽  
L VENTER ◽  
H HEINZE ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Zollinger Ellison Syndrome ◽  
Term Maintenance
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