IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity

Phillip P. Domeier, Sathi Babu Chodisetti, Chetna Soni, Stephanie L. Schell, Melinda J. Elias, Eric B. Wong, Timothy K. Cooper, Daisuke Kitamura, Ziaur S.M. Rahman

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell-intrinsic IFN-γ receptor (IFN-γR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development. We further demonstrate that IFN-γR and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-γ production by B cells. Global or B cell-specific IFN-γR deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG2c and IgG2b auto-Ab titers compared with B6.Sle1b mice. Additionally, we observed that the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell-intrinsic IFN-γR signaling, suggesting that IFN-γR signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-γR deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell-dependent foreign antigens, indicating that IFN-γR signaling regulates autoimmune, but not the foreign antigen-driven, GC and Tfh cell responses. Together, our data define a novel B cell-intrinsic IFN-γR signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus.

Original languageEnglish (US)
Pages (from-to)715-732
Number of pages18
JournalJournal of Experimental Medicine
Volume213
Issue number5
DOIs
StatePublished - Jan 1 2016

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Germinal Center
Autoimmunity
B-Lymphocytes
Antigens
Nuclear Antigens
Autoantigens
Helper-Inducer T-Lymphocytes
Systemic Lupus Erythematosus
Autoantibodies
Pharmacology
T-Lymphocytes
Phenotype
DNA

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Domeier, Phillip P. ; Chodisetti, Sathi Babu ; Soni, Chetna ; Schell, Stephanie L. ; Elias, Melinda J. ; Wong, Eric B. ; Cooper, Timothy K. ; Kitamura, Daisuke ; Rahman, Ziaur S.M. / IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. In: Journal of Experimental Medicine. 2016 ; Vol. 213, No. 5. pp. 715-732.
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abstract = "Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell-intrinsic IFN-γ receptor (IFN-γR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development. We further demonstrate that IFN-γR and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-γ production by B cells. Global or B cell-specific IFN-γR deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG2c and IgG2b auto-Ab titers compared with B6.Sle1b mice. Additionally, we observed that the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell-intrinsic IFN-γR signaling, suggesting that IFN-γR signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-γR deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell-dependent foreign antigens, indicating that IFN-γR signaling regulates autoimmune, but not the foreign antigen-driven, GC and Tfh cell responses. Together, our data define a novel B cell-intrinsic IFN-γR signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus.",
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Domeier, PP, Chodisetti, SB, Soni, C, Schell, SL, Elias, MJ, Wong, EB, Cooper, TK, Kitamura, D & Rahman, ZSM 2016, 'IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity', Journal of Experimental Medicine, vol. 213, no. 5, pp. 715-732. https://doi.org/10.1084/jem.20151722

IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. / Domeier, Phillip P.; Chodisetti, Sathi Babu; Soni, Chetna; Schell, Stephanie L.; Elias, Melinda J.; Wong, Eric B.; Cooper, Timothy K.; Kitamura, Daisuke; Rahman, Ziaur S.M.

In: Journal of Experimental Medicine, Vol. 213, No. 5, 01.01.2016, p. 715-732.

Research output: Contribution to journalArticle

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T1 - IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity

AU - Domeier, Phillip P.

AU - Chodisetti, Sathi Babu

AU - Soni, Chetna

AU - Schell, Stephanie L.

AU - Elias, Melinda J.

AU - Wong, Eric B.

AU - Cooper, Timothy K.

AU - Kitamura, Daisuke

AU - Rahman, Ziaur S.M.

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AB - Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell-intrinsic IFN-γ receptor (IFN-γR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development. We further demonstrate that IFN-γR and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-γ production by B cells. Global or B cell-specific IFN-γR deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG2c and IgG2b auto-Ab titers compared with B6.Sle1b mice. Additionally, we observed that the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell-intrinsic IFN-γR signaling, suggesting that IFN-γR signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-γR deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell-dependent foreign antigens, indicating that IFN-γR signaling regulates autoimmune, but not the foreign antigen-driven, GC and Tfh cell responses. Together, our data define a novel B cell-intrinsic IFN-γR signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus.

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