IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation

Amy V. Paschall, Ruihua Zhang, Chen Feng Qi, Kankana Bardhan, Liang Peng, Geming Lu, Jianjun Yang, Miriam Merad, Tracy McGaha, Gang Zhou, Andrew Mellor, Scott I. Abrams, Herbert C. Morse, Keiko Ozato, Huabao Xiong, Kebin Liu

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

During hematopoiesis, hematopoietic stem cells constantly differentiate into granulocytes and macrophages via a distinct differentiation program that is tightly controlled by myeloid lineage-specific transcription factors. Mice with a null mutation of IFN regulatory factor 8 (IRF8) accumulate CD11b+Gr1+ myeloid cells that phenotypically and functionally resemble tumor-induced myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in myeloid cell lineage differentiation. However, IRF8 is expressed in various types of immune cells, and whether IRF8 functions intrinsically or extrinsically in regulation of myeloid cell lineage differentiation is not fully understood. In this study, we report an intriguing finding that, although IRF8-deficient mice exhibit deregulated myeloid cell differentiation and resultant accumulation of CD11b+Gr1+ MDSCs, surprisingly, mice with IRF8 deficiency only in myeloid cells exhibit no abnormal myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited deregulated myeloid cell differentiation and MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8-deficient T cells, but not GM-CSF-deficient T cells, increased MDSC accumulation in the recipient chimeric mice. Moreover, overexpression of IRF8 decreased GM-CSF expression in T cells. Our data determine that, in addition to its intrinsic function as an apoptosis regulator in myeloid cells, IRF8 also acts extrinsically to repress GM-CSF expression in T cells to control myeloid cell lineage differentiation, revealing a novel mechanism that the adaptive immune component of the immune system regulates the innate immune cell myelopoiesis in vivo.

Original languageEnglish (US)
Pages (from-to)2369-2379
Number of pages11
JournalJournal of Immunology
Volume194
Issue number5
DOIs
StatePublished - Mar 1 2015

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Cell Lineage
Myeloid Cells
Granulocyte-Macrophage Colony-Stimulating Factor
Cell Differentiation
T-Lymphocytes
Myelopoiesis
Adoptive Transfer
Hematopoiesis
Hematopoietic Stem Cells
Granulocytes
Immune System
Transcription Factors
Macrophages
Myeloid-Derived Suppressor Cells
Apoptosis
Mutation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation. / Paschall, Amy V.; Zhang, Ruihua; Qi, Chen Feng; Bardhan, Kankana; Peng, Liang; Lu, Geming; Yang, Jianjun; Merad, Miriam; McGaha, Tracy; Zhou, Gang; Mellor, Andrew; Abrams, Scott I.; Morse, Herbert C.; Ozato, Keiko; Xiong, Huabao; Liu, Kebin.

In: Journal of Immunology, Vol. 194, No. 5, 01.03.2015, p. 2369-2379.

Research output: Contribution to journalArticle

Paschall, AV, Zhang, R, Qi, CF, Bardhan, K, Peng, L, Lu, G, Yang, J, Merad, M, McGaha, T, Zhou, G, Mellor, A, Abrams, SI, Morse, HC, Ozato, K, Xiong, H & Liu, K 2015, 'IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation', Journal of Immunology, vol. 194, no. 5, pp. 2369-2379. https://doi.org/10.4049/jimmunol.1402412
Paschall, Amy V. ; Zhang, Ruihua ; Qi, Chen Feng ; Bardhan, Kankana ; Peng, Liang ; Lu, Geming ; Yang, Jianjun ; Merad, Miriam ; McGaha, Tracy ; Zhou, Gang ; Mellor, Andrew ; Abrams, Scott I. ; Morse, Herbert C. ; Ozato, Keiko ; Xiong, Huabao ; Liu, Kebin. / IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation. In: Journal of Immunology. 2015 ; Vol. 194, No. 5. pp. 2369-2379.
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AU - Paschall, Amy V.

AU - Zhang, Ruihua

AU - Qi, Chen Feng

AU - Bardhan, Kankana

AU - Peng, Liang

AU - Lu, Geming

AU - Yang, Jianjun

AU - Merad, Miriam

AU - McGaha, Tracy

AU - Zhou, Gang

AU - Mellor, Andrew

AU - Abrams, Scott I.

AU - Morse, Herbert C.

AU - Ozato, Keiko

AU - Xiong, Huabao

AU - Liu, Kebin

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N2 - During hematopoiesis, hematopoietic stem cells constantly differentiate into granulocytes and macrophages via a distinct differentiation program that is tightly controlled by myeloid lineage-specific transcription factors. Mice with a null mutation of IFN regulatory factor 8 (IRF8) accumulate CD11b+Gr1+ myeloid cells that phenotypically and functionally resemble tumor-induced myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in myeloid cell lineage differentiation. However, IRF8 is expressed in various types of immune cells, and whether IRF8 functions intrinsically or extrinsically in regulation of myeloid cell lineage differentiation is not fully understood. In this study, we report an intriguing finding that, although IRF8-deficient mice exhibit deregulated myeloid cell differentiation and resultant accumulation of CD11b+Gr1+ MDSCs, surprisingly, mice with IRF8 deficiency only in myeloid cells exhibit no abnormal myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited deregulated myeloid cell differentiation and MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8-deficient T cells, but not GM-CSF-deficient T cells, increased MDSC accumulation in the recipient chimeric mice. Moreover, overexpression of IRF8 decreased GM-CSF expression in T cells. Our data determine that, in addition to its intrinsic function as an apoptosis regulator in myeloid cells, IRF8 also acts extrinsically to repress GM-CSF expression in T cells to control myeloid cell lineage differentiation, revealing a novel mechanism that the adaptive immune component of the immune system regulates the innate immune cell myelopoiesis in vivo.

AB - During hematopoiesis, hematopoietic stem cells constantly differentiate into granulocytes and macrophages via a distinct differentiation program that is tightly controlled by myeloid lineage-specific transcription factors. Mice with a null mutation of IFN regulatory factor 8 (IRF8) accumulate CD11b+Gr1+ myeloid cells that phenotypically and functionally resemble tumor-induced myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in myeloid cell lineage differentiation. However, IRF8 is expressed in various types of immune cells, and whether IRF8 functions intrinsically or extrinsically in regulation of myeloid cell lineage differentiation is not fully understood. In this study, we report an intriguing finding that, although IRF8-deficient mice exhibit deregulated myeloid cell differentiation and resultant accumulation of CD11b+Gr1+ MDSCs, surprisingly, mice with IRF8 deficiency only in myeloid cells exhibit no abnormal myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited deregulated myeloid cell differentiation and MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8-deficient T cells, but not GM-CSF-deficient T cells, increased MDSC accumulation in the recipient chimeric mice. Moreover, overexpression of IRF8 decreased GM-CSF expression in T cells. Our data determine that, in addition to its intrinsic function as an apoptosis regulator in myeloid cells, IRF8 also acts extrinsically to repress GM-CSF expression in T cells to control myeloid cell lineage differentiation, revealing a novel mechanism that the adaptive immune component of the immune system regulates the innate immune cell myelopoiesis in vivo.

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