Basic and Clinical Immunology
TH2 dominance and defective development of a CD8+ dendritic cell subset in Id2-deficient mice,☆☆,

https://doi.org/10.1067/mai.2003.29Get rights and content

Abstract

Background: Although the TH1/TH2 balance is important in many clinical situations, the regulatory mechanisms in vivo have not been well elucidated. Objective: We sought to characterize the immunologic status of mice lacking Id2, an inhibitor of basic helix-loop-helix transcription factors. Methods: We analyzed serum immunoglobulin levels, gene-expression profiles in the spleen, TH1/TH2 balance, and dendritic cell (DC) populations of Id2–/– mice. Results: Serum levels of TH2-mediated IgG1 and IgE were increased more than 10-fold in Id2–/– mice without antigenic stimulation. Gene-expression analysis in Id2–/– splenocytes revealed enhanced expression of TH2-related genes, such as IL-4, and reduced expression of TH1-related genes, including IFN-γ and IL-12. Intracellular cytokine staining also confirmed that Id2–/– splenic CD4+ T cells are substantially skewed to TH2 cells. However, Id2–/– naive CD4+ T cells differentiated into TH1 cells comparably with wild-type T cells under the appropriate culture conditions. Id2–/– mice displayed a selective and remarkable reduction of the CD8α+ DC subset, which is known to induce preferential TH1 differentiation. Conclusion: Id2 is an indispensable regulator of the TH1/TH2 balance, possibly through the proper development of CD8α+ DCs, and could be a novel target to treat allergic diseases. J Allergy Clin Immunol 2003;111:136-42.

Section snippets

Mice

Id2 mutant mice20 were of the 129/Sv genetic background and were reared under specific pathogen-free conditions. Id2+/– mice displayed characteristics similar to those of wild-type litter mates in all experiments conducted unless otherwise specified. All animal procedures described in this study were performed in accordance with the guidelines for animal experiments of Kyoto University Graduate School of Medicine and Graduate School of Biostudies and Fukui Medical University.

Determination of serum levels of IgE and IgG subclasses

Total IgE and IgG

Increased serum levels of TH2-mediated immunoglobulins in Id2–/–mice

To evaluate the immunologic status of Id2–/– mice, we analyzed serum levels of IgE and IgG subclasses in Id2–/– mice by means of ELISA. The levels of IgE and IgG1 were substantially increased (by approximately 20-fold and 10-fold, respectively) in Id2–/– mice compared with those in control mice (Fig 1, A and B ).

. Serum levels of IgE and IgG subclasses in Id2–/– and control mice. Sera were obtained from Id2–/– and control mice aged 10 to 20 weeks, and the levels of IgE (A) and the IgG subclasses

Discussion

In this article we have shown that Id2–/– mice are in a TH2-dominant state and have a selective defect in the CD8+ DC subset. The TH2 dominance in the mutant mice was shown by examining serum immunoglobulin levels and verified with gene-expression analysis in the spleen and intracellular staining of cytokines in splenic CD4+ T cells. We initially speculated that Id2 regulates TH1/TH2 differentiation at the TH0 level as an intrinsic factor. However, purified naive CD4+ T cells of Id2–/– mice

Acknowledgements

We thank Dr S.-I. Nishikawa for helpful support and Dr T. Nishimura for suggestions.

References (41)

  • A Guerriero et al.

    PU.1 is required for myeloid-derived but not lymphoid-derived dendritic cells

    Blood

    (2000)
  • L Wu et al.

    Cell-autonomous defects in dendritic cell populations of Ikaros mutant mice point to a developmental relationship with the lymphoid lineage

    Immunity

    (1997)
  • U Wahn et al.

    Childhood risk factors for atopy and the importance of early intervention

    J Allergy Clin Immunol

    (2001)
  • KM Murphy et al.

    Signaling and transcription in T helper development

    Annu Rev Immunol

    (2000)
  • J Banchereau et al.

    Dendritic cells and the control of immunity

    Nature

    (1998)
  • J Banchereau et al.

    Immunobiology of dendritic cells

    Annu Rev Immunol

    (2000)
  • RM Steinman et al.

    Dendritic cells in the T-cell areas of lymphoid organs

    Immunol Rev

    (1997)
  • D Vremec et al.

    CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen

    J Immunol

    (2000)
  • R Maldonado-López et al.

    CD8α+ and CD8α– subclasses of dendritic cells direct the development of distinct T helper cells in vivo

    J Exp Med

    (1999)
  • H Nakano et al.

    CD11c+B220+Gr-1+ cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells

    J Exp Med

    (2001)
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      Citation Excerpt :

      It has been established that IRF8 can directly drive the progenitors into classic CD8α+ DCs by targeting Id2 and Batf3 (Jaiswal et al., 2013), (Jackson et al., 2011). In Id2−/− mice, it is shown that the percentage of splenic CD8α+ DCs is reduced (Hacker et al., 2003), (Kusunoki et al., 2003). However, another report has demonstrated that Id2 is not essential for the development of CD8α+ DCs (Seillet et al., 2013).

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    Drs Kusunoki and Sugai contributed equally to this work.

    ☆☆

    Supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (T.K.: 13670799, K.I.: B14370075 and 13140202, A.S.: 12206046 and 13206035, Y.Y.: 13470034 and 13037016); the Novartis Foundation and Research Project Funds of Fukui Medical University (Y.Y.); and Special Coordination Funds for Promoting Science and Technology (K.I.).

    Reprint requests: Yoshifumi Yokota, MD, PhD, Department of Biochemistry, Fukui Medical University, 23-3 Shimoaizuki, Matsuoka, Fukui 910-1193, Japan.

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