The transcription factor Runx3 guards cytotoxic CD8 + effector T cells against deviation towards follicular helper T cell lineage

Qiang Shan; Zhouhao Zeng; Shaojun Xing; Fengyin Li; Stacey M. Hartwig; Jodi A. Gullicksrud; Samarchith P. Kurup; Natalija Van Braeckel-Budimir; Yao Su; Matthew D. Martin; Steven M. Varga; Ichiro Taniuchi; John T. Harty; Weiqun Peng; Vladimir P. Badovinac; Hai Hui Xue

doi:10.1038/ni.3773

The transcription factor Runx3 guards cytotoxic CD8 + effector T cells against deviation towards follicular helper T cell lineage

Qiang Shan
, Zhouhao Zeng
, Shaojun Xing
, Fengyin Li
, Stacey M. Hartwig
, Jodi A. Gullicksrud
, Samarchith P. Kurup
, Natalija Van Braeckel-Budimir
, Yao Su
, Matthew D. Martin
, Steven M. Varga
, Ichiro Taniuchi
, John T. Harty
, Weiqun Peng
, Vladimir P. Badovinac
, Hai Hui Xue

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

120 Scopus citations

Abstract

Activated CD8 + T cells differentiate into cytotoxic effector (T EFF) cells that eliminate target cells. How T EFF cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in T EFF cells. Runx3-deficient CD8 + T EFF cells aberrantly upregulated genes characteristic of follicular helper T (T FH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFβ transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the T FH program. Ablating Tcf7 in Runx3-deficient CD8 + T EFF cells prevented the upregulation of T FH genes and ameliorated their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforced acquisition of cytotoxic functions and protected the cytotoxic lineage integrity by preventing T FH -lineage deviation.

Original language	English (US)
Pages (from-to)	931-939
Number of pages	9
Journal	Nature immunology
Volume	18
Issue number	8
DOIs	https://doi.org/10.1038/ni.3773
State	Published - Jul 19 2017
Externally published	Yes

Bibliographical note

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© 2017 Nature America, Inc.Part of Springer Nature All Rights Reserved.

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Shan, Q., Zeng, Z., Xing, S., Li, F., Hartwig, S. M., Gullicksrud, J. A., Kurup, S. P., Van Braeckel-Budimir, N., Su, Y., Martin, M. D., Varga, S. M., Taniuchi, I., Harty, J. T., Peng, W., Badovinac, V. P., & Xue, H. H. (2017). The transcription factor Runx3 guards cytotoxic CD8 + effector T cells against deviation towards follicular helper T cell lineage. Nature immunology, 18(8), 931-939. https://doi.org/10.1038/ni.3773

Shan, Q, Zeng, Z, Xing, S, Li, F, Hartwig, SM, Gullicksrud, JA, Kurup, SP, Van Braeckel-Budimir, N, Su, Y, Martin, MD, Varga, SM, Taniuchi, I, Harty, JT, Peng, W, Badovinac, VP & Xue, HH 2017, 'The transcription factor Runx3 guards cytotoxic CD8 + effector T cells against deviation towards follicular helper T cell lineage', Nature immunology, vol. 18, no. 8, pp. 931-939. https://doi.org/10.1038/ni.3773

@article{db129c89f5b14152b1c75443968b2fd0,

title = "The transcription factor Runx3 guards cytotoxic CD8 + effector T cells against deviation towards follicular helper T cell lineage",

abstract = "Activated CD8 + T cells differentiate into cytotoxic effector (T EFF) cells that eliminate target cells. How T EFF cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in T EFF cells. Runx3-deficient CD8 + T EFF cells aberrantly upregulated genes characteristic of follicular helper T (T FH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFβ transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the T FH program. Ablating Tcf7 in Runx3-deficient CD8 + T EFF cells prevented the upregulation of T FH genes and ameliorated their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforced acquisition of cytotoxic functions and protected the cytotoxic lineage integrity by preventing T FH -lineage deviation.",

author = "Qiang Shan and Zhouhao Zeng and Shaojun Xing and Fengyin Li and Hartwig, \{Stacey M.\} and Gullicksrud, \{Jodi A.\} and Kurup, \{Samarchith P.\} and \{Van Braeckel-Budimir\}, Natalija and Yao Su and Martin, \{Matthew D.\} and Varga, \{Steven M.\} and Ichiro Taniuchi and Harty, \{John T.\} and Weiqun Peng and Badovinac, \{Vladimir P.\} and Xue, \{Hai Hui\}",

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AU - Shan, Qiang

AU - Zeng, Zhouhao

AU - Xing, Shaojun

AU - Li, Fengyin

AU - Hartwig, Stacey M.

AU - Gullicksrud, Jodi A.

AU - Kurup, Samarchith P.

AU - Van Braeckel-Budimir, Natalija

AU - Su, Yao

AU - Martin, Matthew D.

AU - Varga, Steven M.

AU - Taniuchi, Ichiro

AU - Harty, John T.

AU - Peng, Weiqun

AU - Badovinac, Vladimir P.

AU - Xue, Hai Hui

PY - 2017/7/19

Y1 - 2017/7/19

N2 - Activated CD8 + T cells differentiate into cytotoxic effector (T EFF) cells that eliminate target cells. How T EFF cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in T EFF cells. Runx3-deficient CD8 + T EFF cells aberrantly upregulated genes characteristic of follicular helper T (T FH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFβ transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the T FH program. Ablating Tcf7 in Runx3-deficient CD8 + T EFF cells prevented the upregulation of T FH genes and ameliorated their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforced acquisition of cytotoxic functions and protected the cytotoxic lineage integrity by preventing T FH -lineage deviation.

AB - Activated CD8 + T cells differentiate into cytotoxic effector (T EFF) cells that eliminate target cells. How T EFF cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in T EFF cells. Runx3-deficient CD8 + T EFF cells aberrantly upregulated genes characteristic of follicular helper T (T FH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFβ transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the T FH program. Ablating Tcf7 in Runx3-deficient CD8 + T EFF cells prevented the upregulation of T FH genes and ameliorated their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforced acquisition of cytotoxic functions and protected the cytotoxic lineage integrity by preventing T FH -lineage deviation.

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The transcription factor Runx3 guards cytotoxic CD8 + effector T cells against deviation towards follicular helper T cell lineage

Abstract

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