BACH2 regulates CD8 + T cell differentiation by controlling access of AP-1 factors to enhancers

Rahul Roychoudhuri; David Clever; Peng Li; Yoshiyuki Wakabayashi; Kylie M. Quinn; Christopher A. Klebanoff; Yun Ji; Madhusudhanan Sukumar; Robert L. Eil; Zhiya Yu; Rosanne Spolski; Douglas C. Palmer; Jenny H. Pan; Shashank J. Patel; Derek C. Macallan; Giulia Fabozzi; Han Yu Shih; Yuka Kanno; Akihiko Muto; Jun Zhu; Luca Gattinoni; John J. O'Shea; Klaus Okkenhaug; Kazuhiko Igarashi; Warren J. Leonard; Nicholas P. Restifo

doi:10.1038/ni.3441

BACH2 regulates CD8 + T cell differentiation by controlling access of AP-1 factors to enhancers

Rahul Roychoudhuri, David Clever, Peng Li, Yoshiyuki Wakabayashi, Kylie M. Quinn, Christopher A. Klebanoff, Yun Ji, Madhusudhanan Sukumar, Robert L. Eil, Zhiya Yu, Rosanne Spolski, Douglas C. Palmer, Jenny H. Pan, Shashank J. Patel, Derek C. Macallan, Giulia Fabozzi, Han Yu Shih, Yuka Kanno, Akihiko Muto, Jun ZhuLuca Gattinoni, John J. O'Shea, Klaus Okkenhaug, Kazuhiko Igarashi, Warren J. Leonard, Nicholas P. Restifo

MED - Medical Sciences

Research output: Contribution to journal › Article › peer-review

153 Citations (Scopus)

Abstract

T cell antigen receptor (TCR) signaling drives distinct responses depending on the differentiation state and context of CD8 + T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection. BACH2 was recruited to enhancers, where it limited expression of TCR-driven genes by attenuating the availability of activator protein-1 (AP-1) sites to Jun family signal-dependent TFs. In naive cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs.

Original language	English
Pages (from-to)	851-860
Number of pages	10
Journal	Nature Immunology
Volume	17
Issue number	7
DOIs	https://doi.org/10.1038/ni.3441
Publication status	Published - 2016 Jun 21

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Roychoudhuri, R., Clever, D., Li, P., Wakabayashi, Y., Quinn, K. M., Klebanoff, C. A., Ji, Y., Sukumar, M., Eil, R. L., Yu, Z., Spolski, R., Palmer, D. C., Pan, J. H., Patel, S. J., Macallan, D. C., Fabozzi, G., Shih, H. Y., Kanno, Y., Muto, A., ... Restifo, N. P. (2016). BACH2 regulates CD8 + T cell differentiation by controlling access of AP-1 factors to enhancers. Nature Immunology, 17(7), 851-860. https://doi.org/10.1038/ni.3441

Roychoudhuri, R, Clever, D, Li, P, Wakabayashi, Y, Quinn, KM, Klebanoff, CA, Ji, Y, Sukumar, M, Eil, RL, Yu, Z, Spolski, R, Palmer, DC, Pan, JH, Patel, SJ, Macallan, DC, Fabozzi, G, Shih, HY, Kanno, Y, Muto, A, Zhu, J, Gattinoni, L, O'Shea, JJ, Okkenhaug, K, Igarashi, K, Leonard, WJ & Restifo, NP 2016, 'BACH2 regulates CD8 + T cell differentiation by controlling access of AP-1 factors to enhancers', Nature Immunology, vol. 17, no. 7, pp. 851-860. https://doi.org/10.1038/ni.3441

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title = "BACH2 regulates CD8 + T cell differentiation by controlling access of AP-1 factors to enhancers",

abstract = "T cell antigen receptor (TCR) signaling drives distinct responses depending on the differentiation state and context of CD8 + T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection. BACH2 was recruited to enhancers, where it limited expression of TCR-driven genes by attenuating the availability of activator protein-1 (AP-1) sites to Jun family signal-dependent TFs. In naive cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs.",

author = "Rahul Roychoudhuri and David Clever and Peng Li and Yoshiyuki Wakabayashi and Quinn, {Kylie M.} and Klebanoff, {Christopher A.} and Yun Ji and Madhusudhanan Sukumar and Eil, {Robert L.} and Zhiya Yu and Rosanne Spolski and Palmer, {Douglas C.} and Pan, {Jenny H.} and Patel, {Shashank J.} and Macallan, {Derek C.} and Giulia Fabozzi and Shih, {Han Yu} and Yuka Kanno and Akihiko Muto and Jun Zhu and Luca Gattinoni and O'Shea, {John J.} and Klaus Okkenhaug and Kazuhiko Igarashi and Leonard, {Warren J.} and Restifo, {Nicholas P.}",

note = "Funding Information: Supported by the Intramural Research Programs of the NCI and NHLBI, Wellcome Trust/Royal Society grant 105663/Z/14/Z (R.R.) and UK Biotechnology and Biological Sciences Research Council grant BB/N007794/1 (R.R. and K.O.). Publisher Copyright: {\textcopyright} 2016 Nature America, Inc. All rights reserved.",

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doi = "10.1038/ni.3441",

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AU - Clever, David

AU - Li, Peng

AU - Wakabayashi, Yoshiyuki

AU - Quinn, Kylie M.

AU - Klebanoff, Christopher A.

AU - Ji, Yun

AU - Sukumar, Madhusudhanan

AU - Eil, Robert L.

AU - Yu, Zhiya

AU - Spolski, Rosanne

AU - Palmer, Douglas C.

AU - Pan, Jenny H.

AU - Patel, Shashank J.

AU - Macallan, Derek C.

AU - Fabozzi, Giulia

AU - Shih, Han Yu

AU - Kanno, Yuka

AU - Muto, Akihiko

AU - Zhu, Jun

AU - Gattinoni, Luca

AU - O'Shea, John J.

AU - Okkenhaug, Klaus

AU - Igarashi, Kazuhiko

AU - Leonard, Warren J.

AU - Restifo, Nicholas P.

N1 - Funding Information: Supported by the Intramural Research Programs of the NCI and NHLBI, Wellcome Trust/Royal Society grant 105663/Z/14/Z (R.R.) and UK Biotechnology and Biological Sciences Research Council grant BB/N007794/1 (R.R. and K.O.). Publisher Copyright: © 2016 Nature America, Inc. All rights reserved.

PY - 2016/6/21

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N2 - T cell antigen receptor (TCR) signaling drives distinct responses depending on the differentiation state and context of CD8 + T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection. BACH2 was recruited to enhancers, where it limited expression of TCR-driven genes by attenuating the availability of activator protein-1 (AP-1) sites to Jun family signal-dependent TFs. In naive cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs.

AB - T cell antigen receptor (TCR) signaling drives distinct responses depending on the differentiation state and context of CD8 + T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection. BACH2 was recruited to enhancers, where it limited expression of TCR-driven genes by attenuating the availability of activator protein-1 (AP-1) sites to Jun family signal-dependent TFs. In naive cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs.

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BACH2 regulates CD8 + T cell differentiation by controlling access of AP-1 factors to enhancers

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