Graded Expression of Interferon Regulatory Factor-4 Coordinates Isotype Switching with Plasma Cell Differentiation

Roger Sciammas; A. L. Shaffer; Jonathan H. Schatz; Hong Zhao; Louis M. Staudt; Harinder Singh

doi:10.1016/j.immuni.2006.07.009

Graded Expression of Interferon Regulatory Factor-4 Coordinates Isotype Switching with Plasma Cell Differentiation

Roger Sciammas, A. L. Shaffer, Jonathan H. Schatz, Hong Zhao, Louis M. Staudt, Harinder Singh

Medicine

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

454 Scopus citations

Abstract

Molecular mechanisms underlying the coordination of isotype switching with plasma cell differentiation are poorly understood. We show that interferon regulatory factor-4 (IRF-4) regulates both processes by controlling the expression of the Aicda and Prdm1 genes, which encode AID and Blimp-1, respectively. Genome-wide analysis demonstrated that Irf4^-/- B cells failed to induce the entire Blimp-1-dependent plasma cell program. Restoration of AID or Blimp-1 expression in Irf4^-/- B cells promoted isotype switching or secretion, respectively. IRF-4 was expressed in a graded manner in differentiating B cells and targeted Prdm1. Higher concentration of IRF-4 induced Prdm1 and consequently the transition from a germinal center gene expression program to that of a plasma cell. We propose a gene-regulatory network in which graded expression of IRF-4 developmentally coordinates isotype switching with plasma cell differentiation.

Original language	English (US)
Pages (from-to)	225-236
Number of pages	12
Journal	Immunity
Volume	25
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2006.07.009
State	Published - Aug 2006

Keywords

DNA
MOLIMMUNO
SIGNALING

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2006.07.009

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title = "Graded Expression of Interferon Regulatory Factor-4 Coordinates Isotype Switching with Plasma Cell Differentiation",

abstract = "Molecular mechanisms underlying the coordination of isotype switching with plasma cell differentiation are poorly understood. We show that interferon regulatory factor-4 (IRF-4) regulates both processes by controlling the expression of the Aicda and Prdm1 genes, which encode AID and Blimp-1, respectively. Genome-wide analysis demonstrated that Irf4-/- B cells failed to induce the entire Blimp-1-dependent plasma cell program. Restoration of AID or Blimp-1 expression in Irf4-/- B cells promoted isotype switching or secretion, respectively. IRF-4 was expressed in a graded manner in differentiating B cells and targeted Prdm1. Higher concentration of IRF-4 induced Prdm1 and consequently the transition from a germinal center gene expression program to that of a plasma cell. We propose a gene-regulatory network in which graded expression of IRF-4 developmentally coordinates isotype switching with plasma cell differentiation.",

keywords = "DNA, MOLIMMUNO, SIGNALING",

author = "Roger Sciammas and Shaffer, {A. L.} and Schatz, {Jonathan H.} and Hong Zhao and Staudt, {Louis M.} and Harinder Singh",

note = "Funding Information: We are grateful to members of the Singh laboratory for meaningful discussions. The Immunology Applications Core Facility at The University of Chicago provided valuable advice in performing flow cytometric analysis and sorting. We thank D. Schatz (Yale U.) for providing the CD40L-expressing baculovirus and L. Corcoran (WEHI) for the anti-Blimp-1 monoclonal. We gratefully acknowledge discussions with A. Warmflash and A. Dinner concerning the gene regulatory network. A.L.S. and L.M.S. are supported by the Intramural Research Program of the NIH, National Cancer Institute, and Center for Cancer Research. H.S. is an Investigator with the Howard Hughes Medical Institute. ",

year = "2006",

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doi = "10.1016/j.immuni.2006.07.009",

language = "English (US)",

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pages = "225--236",

journal = "Immunity",

issn = "1074-7613",

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AU - Sciammas, Roger

AU - Shaffer, A. L.

AU - Schatz, Jonathan H.

AU - Zhao, Hong

AU - Staudt, Louis M.

AU - Singh, Harinder

N1 - Funding Information: We are grateful to members of the Singh laboratory for meaningful discussions. The Immunology Applications Core Facility at The University of Chicago provided valuable advice in performing flow cytometric analysis and sorting. We thank D. Schatz (Yale U.) for providing the CD40L-expressing baculovirus and L. Corcoran (WEHI) for the anti-Blimp-1 monoclonal. We gratefully acknowledge discussions with A. Warmflash and A. Dinner concerning the gene regulatory network. A.L.S. and L.M.S. are supported by the Intramural Research Program of the NIH, National Cancer Institute, and Center for Cancer Research. H.S. is an Investigator with the Howard Hughes Medical Institute.

PY - 2006/8

Y1 - 2006/8

N2 - Molecular mechanisms underlying the coordination of isotype switching with plasma cell differentiation are poorly understood. We show that interferon regulatory factor-4 (IRF-4) regulates both processes by controlling the expression of the Aicda and Prdm1 genes, which encode AID and Blimp-1, respectively. Genome-wide analysis demonstrated that Irf4-/- B cells failed to induce the entire Blimp-1-dependent plasma cell program. Restoration of AID or Blimp-1 expression in Irf4-/- B cells promoted isotype switching or secretion, respectively. IRF-4 was expressed in a graded manner in differentiating B cells and targeted Prdm1. Higher concentration of IRF-4 induced Prdm1 and consequently the transition from a germinal center gene expression program to that of a plasma cell. We propose a gene-regulatory network in which graded expression of IRF-4 developmentally coordinates isotype switching with plasma cell differentiation.

AB - Molecular mechanisms underlying the coordination of isotype switching with plasma cell differentiation are poorly understood. We show that interferon regulatory factor-4 (IRF-4) regulates both processes by controlling the expression of the Aicda and Prdm1 genes, which encode AID and Blimp-1, respectively. Genome-wide analysis demonstrated that Irf4-/- B cells failed to induce the entire Blimp-1-dependent plasma cell program. Restoration of AID or Blimp-1 expression in Irf4-/- B cells promoted isotype switching or secretion, respectively. IRF-4 was expressed in a graded manner in differentiating B cells and targeted Prdm1. Higher concentration of IRF-4 induced Prdm1 and consequently the transition from a germinal center gene expression program to that of a plasma cell. We propose a gene-regulatory network in which graded expression of IRF-4 developmentally coordinates isotype switching with plasma cell differentiation.

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Graded Expression of Interferon Regulatory Factor-4 Coordinates Isotype Switching with Plasma Cell Differentiation

Abstract

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