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

41 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

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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

The transcription factor Runx3 guards cytotoxic CD8 + effector T cells against deviation towards follicular helper T cell lineage. / Shan, Qiang; Zeng, Zhouhao; Xing, Shaojun; Li, Fengyin; Hartwig, Stacey M.; Gullicksrud, Jodi A.; Kurup, Samarchith P.; Van Braeckel-Budimir, Natalija; Su, Yao; Martin, Matthew D.; Varga, Steven M.; Taniuchi, Ichiro; Harty, John T.; Peng, Weiqun; Badovinac, Vladimir P.; Xue, Hai Hui.

In: Nature immunology, Vol. 18, No. 8, 19.07.2017, p. 931-939.

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

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

Shan, Qiang ; Zeng, Zhouhao ; Xing, Shaojun ; Li, Fengyin ; Hartwig, Stacey M. ; Gullicksrud, Jodi A. ; Kurup, Samarchith P. ; Van Braeckel-Budimir, Natalija ; Su, Yao ; Martin, Matthew D. ; Varga, Steven M. ; Taniuchi, Ichiro ; Harty, John T. ; Peng, Weiqun ; Badovinac, Vladimir P. ; Xue, Hai Hui. / The transcription factor Runx3 guards cytotoxic CD8 + effector T cells against deviation towards follicular helper T cell lineage. In: Nature immunology. 2017 ; Vol. 18, No. 8. pp. 931-939.

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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.",

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AU - Varga, Steven M.

AU - Taniuchi, Ichiro

AU - Harty, John T.

AU - Peng, Weiqun

AU - Badovinac, Vladimir P.

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

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