STAT6 and furin are successive triggers for the production of TGF-β by T cells

Yue Li; Weiren Liu; Xiaqun Guan; Jamie Truscott; John W. Creemers; Hung Lin Chen; Marko Pesu; Rami G.El Abiad; Bahri Karacay; Joseph F. Urban; David E. Elliott; Mark H. Kaplan; Bruce R. Blazar; M. Nedim Ince

doi:10.4049/jimmunol.1700808

STAT6 and furin are successive triggers for the production of TGF-β by T cells

Yue Li, Weiren Liu, Xiaqun Guan, Jamie Truscott, John W. Creemers, Hung Lin Chen, Marko Pesu, Rami G.El Abiad, Bahri Karacay, Joseph F. Urban, David E. Elliott, Mark H. Kaplan, Bruce R. Blazar, M. Nedim Ince

Pediatrics - Blood/Marrow Transplant

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

9 Scopus citations

Abstract

Production of TGF-β by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-β generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-β generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin.

Original language	English (US)
Pages (from-to)	2612-2623
Number of pages	12
Journal	Journal of Immunology
Volume	201
Issue number	9
DOIs	https://doi.org/10.4049/jimmunol.1700808
State	Published - Nov 1 2018

Bibliographical note

Funding Information:
This work was supported by research funds from the National Institutes of Health R56 AI 116715 (to M.N.I.), R01 HL56067, AI34495, HL11879 (to B.R.B.), and R01 AI095282 (to M.H.K.), the Department of Veterans Affairs BX002906 (to M.N.I.) and BX002715 (to D.E.E.), Research Foundation - Flanders G.0738.15N, Belgium (to J.W.C.), the Sigrid Juselius Foundation, and the Academy of Finland (to M.P.).

Publisher Copyright:
© 2018 by The American Association of Immunologists, Inc.

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title = "STAT6 and furin are successive triggers for the production of TGF-β by T cells",

abstract = "Production of TGF-β by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-β generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-β generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin.",

author = "Yue Li and Weiren Liu and Xiaqun Guan and Jamie Truscott and Creemers, {John W.} and Chen, {Hung Lin} and Marko Pesu and Abiad, {Rami G.El} and Bahri Karacay and Urban, {Joseph F.} and Elliott, {David E.} and Kaplan, {Mark H.} and Blazar, {Bruce R.} and {Nedim Ince}, M.",

note = "Funding Information: This work was supported by research funds from the National Institutes of Health R56 AI 116715 (to M.N.I.), R01 HL56067, AI34495, HL11879 (to B.R.B.), and R01 AI095282 (to M.H.K.), the Department of Veterans Affairs BX002906 (to M.N.I.) and BX002715 (to D.E.E.), Research Foundation - Flanders G.0738.15N, Belgium (to J.W.C.), the Sigrid Juselius Foundation, and the Academy of Finland (to M.P.). Publisher Copyright: {\textcopyright} 2018 by The American Association of Immunologists, Inc.",

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AU - Li, Yue

AU - Liu, Weiren

AU - Guan, Xiaqun

AU - Truscott, Jamie

AU - Creemers, John W.

AU - Chen, Hung Lin

AU - Pesu, Marko

AU - Abiad, Rami G.El

AU - Karacay, Bahri

AU - Urban, Joseph F.

AU - Elliott, David E.

AU - Kaplan, Mark H.

AU - Blazar, Bruce R.

AU - Nedim Ince, M.

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PY - 2018/11/1

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N2 - Production of TGF-β by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-β generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-β generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin.

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STAT6 and furin are successive triggers for the production of TGF-β by T cells

Abstract

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