TET2 and 3 proteins control iNKT cell lineage specification and TCR mediated expansion

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TET2 and 3 proteins control iNKT cell lineage specification and TCR mediated expansion. / Tsagaratou, Ageliki; Avalos, Edahi Gonzalez; Rautio, Sini; Browne, James Scott; Togher, Susan; Pastor, William; Rothenberg, Ellen V.; Lahdesmaki, Harri; Rao, Anjana.

In: JOURNAL OF IMMUNOLOGY, Vol. 198, No. 1, Supplement, 2017, p. 215.11.

Research output: Contribution to journalArticle

Harvard

Tsagaratou, A, Avalos, EG, Rautio, S, Browne, JS, Togher, S, Pastor, W, Rothenberg, EV, Lahdesmaki, H & Rao, A 2017, 'TET2 and 3 proteins control iNKT cell lineage specification and TCR mediated expansion', JOURNAL OF IMMUNOLOGY, vol. 198, no. 1, Supplement, pp. 215.11.

APA

Tsagaratou, A., Avalos, E. G., Rautio, S., Browne, J. S., Togher, S., Pastor, W., ... Rao, A. (2017). TET2 and 3 proteins control iNKT cell lineage specification and TCR mediated expansion. JOURNAL OF IMMUNOLOGY, 198(1, Supplement), 215.11.

Vancouver

Tsagaratou A, Avalos EG, Rautio S, Browne JS, Togher S, Pastor W et al. TET2 and 3 proteins control iNKT cell lineage specification and TCR mediated expansion. JOURNAL OF IMMUNOLOGY. 2017;198(1, Supplement):215.11.

Author

Tsagaratou, Ageliki ; Avalos, Edahi Gonzalez ; Rautio, Sini ; Browne, James Scott ; Togher, Susan ; Pastor, William ; Rothenberg, Ellen V. ; Lahdesmaki, Harri ; Rao, Anjana. / TET2 and 3 proteins control iNKT cell lineage specification and TCR mediated expansion. In: JOURNAL OF IMMUNOLOGY. 2017 ; Vol. 198, No. 1, Supplement. pp. 215.11.

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@article{c8e0d997bafb416da033f1d58cd2512e,
title = "TET2 and 3 proteins control iNKT cell lineage specification and TCR mediated expansion",
abstract = "TET proteins are 2-oxoglutarate- and Fe(II) dependent dioxygenases that catalyze the hydroxylation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products (5-formylcytosine and 5-carboxylcytosine) in DNA. They can act as mediators of textquotedblleftactivetextquotedblright (replication-independent) DNA demethylation, achieved through excision of 5fC and 5caC by thymine DNA glycosylase (TDG) followed by replacement with an unmethylated cytosine by base excision repair. They are also novel epigenetic marks that are recognized specifically by readers.The role of TET proteins in developing thymocytes remains elusive. In the present study, we show that simultaneous deletion of TET2 and TET3 in mice (DKO) results in aberrant development of invariant NKT cells that are skewed towards the NKT17 lineage. We also found upregulation of proliferation controlling genes as well as genes that are normally expressed in precursor cells. This results in an unprecedented expansion of iNKT cells, leading to lethality. The expansion is driven by antigen recognition, since the disease is effectively transmitted to fully immunocompetent recipient mice only if they express CD1d, a non-classical MHC protein that presents lipid antigens to iNKT cells. Molecular analysis revealed that TET2 and TET3 drive iNKT lineage specific DNA demethylation and control gene expression via DNA demethylation and/or chromatin accessibility of key lineage specifying factors such as RORgt, Tbet and ThPOK.Collectively, TET2 and TET3 are fundamental regulators that seal iNKT lineage fate, ensure proper development and maturation and safeguard aberrant TCR mediated expansion.",
author = "Ageliki Tsagaratou and Avalos, {Edahi Gonzalez} and Sini Rautio and Browne, {James Scott} and Susan Togher and William Pastor and Rothenberg, {Ellen V.} and Harri Lahdesmaki and Anjana Rao",
year = "2017",
language = "English",
volume = "198",
pages = "215.11",
journal = "JOURNAL OF IMMUNOLOGY",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "1, Supplement",

}

RIS - Download

TY - JOUR

T1 - TET2 and 3 proteins control iNKT cell lineage specification and TCR mediated expansion

AU - Tsagaratou, Ageliki

AU - Avalos, Edahi Gonzalez

AU - Rautio, Sini

AU - Browne, James Scott

AU - Togher, Susan

AU - Pastor, William

AU - Rothenberg, Ellen V.

AU - Lahdesmaki, Harri

AU - Rao, Anjana

PY - 2017

Y1 - 2017

N2 - TET proteins are 2-oxoglutarate- and Fe(II) dependent dioxygenases that catalyze the hydroxylation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products (5-formylcytosine and 5-carboxylcytosine) in DNA. They can act as mediators of textquotedblleftactivetextquotedblright (replication-independent) DNA demethylation, achieved through excision of 5fC and 5caC by thymine DNA glycosylase (TDG) followed by replacement with an unmethylated cytosine by base excision repair. They are also novel epigenetic marks that are recognized specifically by readers.The role of TET proteins in developing thymocytes remains elusive. In the present study, we show that simultaneous deletion of TET2 and TET3 in mice (DKO) results in aberrant development of invariant NKT cells that are skewed towards the NKT17 lineage. We also found upregulation of proliferation controlling genes as well as genes that are normally expressed in precursor cells. This results in an unprecedented expansion of iNKT cells, leading to lethality. The expansion is driven by antigen recognition, since the disease is effectively transmitted to fully immunocompetent recipient mice only if they express CD1d, a non-classical MHC protein that presents lipid antigens to iNKT cells. Molecular analysis revealed that TET2 and TET3 drive iNKT lineage specific DNA demethylation and control gene expression via DNA demethylation and/or chromatin accessibility of key lineage specifying factors such as RORgt, Tbet and ThPOK.Collectively, TET2 and TET3 are fundamental regulators that seal iNKT lineage fate, ensure proper development and maturation and safeguard aberrant TCR mediated expansion.

AB - TET proteins are 2-oxoglutarate- and Fe(II) dependent dioxygenases that catalyze the hydroxylation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products (5-formylcytosine and 5-carboxylcytosine) in DNA. They can act as mediators of textquotedblleftactivetextquotedblright (replication-independent) DNA demethylation, achieved through excision of 5fC and 5caC by thymine DNA glycosylase (TDG) followed by replacement with an unmethylated cytosine by base excision repair. They are also novel epigenetic marks that are recognized specifically by readers.The role of TET proteins in developing thymocytes remains elusive. In the present study, we show that simultaneous deletion of TET2 and TET3 in mice (DKO) results in aberrant development of invariant NKT cells that are skewed towards the NKT17 lineage. We also found upregulation of proliferation controlling genes as well as genes that are normally expressed in precursor cells. This results in an unprecedented expansion of iNKT cells, leading to lethality. The expansion is driven by antigen recognition, since the disease is effectively transmitted to fully immunocompetent recipient mice only if they express CD1d, a non-classical MHC protein that presents lipid antigens to iNKT cells. Molecular analysis revealed that TET2 and TET3 drive iNKT lineage specific DNA demethylation and control gene expression via DNA demethylation and/or chromatin accessibility of key lineage specifying factors such as RORgt, Tbet and ThPOK.Collectively, TET2 and TET3 are fundamental regulators that seal iNKT lineage fate, ensure proper development and maturation and safeguard aberrant TCR mediated expansion.

M3 - Article

VL - 198

SP - 215.11

JO - JOURNAL OF IMMUNOLOGY

JF - JOURNAL OF IMMUNOLOGY

SN - 0022-1767

IS - 1, Supplement

ER -

ID: 16823069