Homeostatic Proliferation of Mature T Cells

Martin, Christopher E.; Frimpong-Boateng, Kwesi; Spasova, Darina; Stone, John C; Surh, Charles D.

doi:10.1007/978-1-62703-290-2_9

Cited by 11 publications

(19 citation statements)

References 43 publications

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“…Magnetic-activated cell sorting (MACS) of CD4 + T cells was carried out using biotinylated antibodies to deplete unwanted cells types as described in ref. 59. Streptavidin-coated IMag beads (BD Bioscience) were used to deplete labeled cells.…”

Section: Ptpn22mentioning

confidence: 99%

PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection

Maine

Teijaro

Marquardt

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The protein encoded by the autoimmune-associated protein tyrosine phosphatase nonreceptor type 22 gene, PTPN22, has wide-ranging effects in immune cells including suppression of T-cell receptor signaling and promoting efficient production of type I interferons (IFN-I) by myeloid cells. Here we show that mice deficient in PTPN22 resist chronic viral infection with lymphocytic choriomeningitis virus clone 13 (LCMV cl13). The numbers and function of viral-specific CD4 T lymphocytes is greatly enhanced, whereas expression of the IFNβ-induced IL-2 repressor, cAMP-responsive element modulator (CREM) is reduced. Reduction of CREM expression in wild-type CD4 T lymphocytes prevents the loss of IL-2 production by CD4 T lymphocytes during infection with LCMV cl13. These findings implicate the IFNβ/CREM/IL-2 axis in regulating T-lymphocyte function during chronic viral infection.

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Section: Ptpn22mentioning

confidence: 99%

PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection

Maine

Teijaro

Marquardt

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Where indicated, CD8 1 T cells were enriched from donor LNs to .95% purity as previously described. 28,31 Treatment with pertussis toxin (PTX) was performed by incubating 4 3 10 7 cells/mL in RPMI containing 0.1M N-2-hydroxyethylpiperazine-N9-2-ethanesulfonic acid and 2% fetal calf serum with 100 ng/mL PTX (List Biological Laboratories, Campbell, CA) for 2 hours at 37°C, and washed .4 times. Donor cells were labeled with 5 mM of either carboxyfluorescein diacetate succinimidyl ester (CFSE) or CellTrace Violet (CTV) (both from Molecular Probes), as previously described, 28 and intravenously injected into host mice.…”

Section: Adoptive Transfer Of T-cell Subsets or Whole Lymphocytesmentioning

confidence: 99%

“…Cells (2 3 10 6 ) from host spleen and pooled LNs were stained for flow cytometry, as previously described, 14,28,31 with mAbs from Biolegend and/ or eBioscience. Data from the stained cells were collected with a BD LSR-II flow cytometer and analyzed by using FlowJo (Treestar).…”

Section: Flow Cytometry and Analysis Of Cellular Recoveriesmentioning

confidence: 99%

“…Bone marrow (BM) chimeras were generated as described. 28 Where indicated, host mice were treated with FTY720 at a dose of 3 mg/kg dissolved in 13 phosphate-buffered saline 1 0.1% bovine serum albumin by intraperitoneal injection on days 21 and 3 of 7-day experiments. Experiments involving the use of animals were approved by the Institutional Animal Care and Use Committees at The Scripps Research Institute and the La Jolla Institute for Allergy and Immunology.…”

Section: Introductionmentioning

confidence: 99%

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IL-7/anti–IL-7 mAb complexes augment cytokine potency in mice through association with IgG-Fc and by competition with IL-7R

Martin

Leeuwen

et al. 2013

Blood

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Key Points• IL-7/antibody complexes are potent because they prolong IL-7 availability in vivo by decreasing specific and nonspecific consumption.Interleukin-7 (IL-7) is essential to T-cell survival as well as homeostatic proliferation, and clinical trials that exploit the mitogenic effects of IL-7 have achieved success in treating human diseases. In mice, the in vivo potency of IL-7 improves dramatically when it is administered as a complex with the anti-IL-7 neutralizing monoclonal antibody clone M25. However, the mechanism whereby M25 augments IL-7 potency is unknown. We have analyzed the discrete contributions of the antibody constant (Fc) and IL-7-binding (Fab) domains to the mechanism. By engaging the neonatal Fc receptor the Fc domain extends the in vivo lifespan of IL-7/M25 complexes and accounts for the majority of their activity. Unexpectedly, the IL-7-neutralizing Fab domain provides an additional, albeit smaller, contribution, possibly by serving as a cytokine depot. This study is the first to demonstrate that the neutralizing aspect of the monoclonal antibody is directly involved in enhancing the potency of a cytokine with a single form of receptor. Lessons from the mechanism of IL-7/M25 complexes inform the design of nextgeneration cytokine therapeutics. (Blood. 2013;121(22):4484-4492)

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“…We next sought to investigate whether Mettl3 −/− naïve T cells were capable of proliferation and could demonstrate normal survival after transfer into Rag2 −/− mice 8 . Using CellTrace labeling of the transferred naïve T cells, proliferation of WT cells was observable beginning week 2, whereas Mettl3 KO T cells retained a naïve phonotype and proliferated slowly.…”

mentioning

confidence: 99%

m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways

Tong

Zhu

et al. 2017

Nature

749

820

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N6 -methyladenosine (m6A) is the most common and abundant messenger RNA modification, modulated by ‘writers’, ‘erasers’ and ‘readers’ of this mark 1,2. In vitro data have shown that m6A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates 3,4. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that deletion of m6A ‘writer’ protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopenic mouse adoptive transfer model, naive Mettl3 deficient T cells failed to undergo homeostatic expansion and remarkably remained in the naïve state up through 12 weeks, thereby preventing colitis. Consistent with these observations, the mRNAs of SOCS family genes encoding STAT- signaling inhibitory proteins, Socs1, Socs3 and Cish, were marked by m6A, exhibited slower mRNA decay and increased mRNAs and protein expression levels in Mettl3 deficient naïve T cells. This increased SOCS family activity consequently inhibited IL-7 mediated STAT5 activation and T cell homeostatic proliferation and differentiation. We also found that m6A plays important roles for inducible degradation of Socs mRNAs in response to IL-7 signaling in order to reprogram Naïve T cells for proliferation and differentiation. Our study elucidates for the first time the in vivo biological role of m6A modification in T cell mediated pathogenesis and reveals a novel mechanism of T cell homeostasis and signal-dependent induction of mRNA degradation.

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Homeostatic Proliferation of Mature T Cells

Cited by 11 publications

References 43 publications

PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection

PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection

IL-7/anti–IL-7 mAb complexes augment cytokine potency in mice through association with IgG-Fc and by competition with IL-7R

m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways

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