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Dysregulation of humoral immunity in Foxp3 conditional-knockout mice

Author:
Tai, Yuki, Sakamoto, Kazuki, Takano, Azumi, Haga, Katsura, Harada, Yohsuke
Source:
Biochemical and biophysical research communications 2019 v.513 no.4 pp. 787-793
ISSN:
0006-291X
Subject:
B-lymphocytes, CD4-positive T-lymphocytes, adults, antibody formation, autoimmune diseases, autoimmunity, cell differentiation, death, genes, humoral immunity, immunoglobulin E, interferon-gamma, interleukin-4, ligands, lymph nodes, mice, oral administration, screening, tamoxifen, therapeutics
Abstract:
Foxp3+ regulatory T cells (Tregs) are crucial for maintaining tolerance to self-antigens and preventing autoimmune diseases. Loss of Foxp3 expression leads to autoimmunity and disrupts humoral immune responses, including hyperproduction of immunoglobulin E (IgE). Elucidation of how Tregs control antibody production can lead to the development of new therapies for autoimmune and allergic diseases. However, premature death of Foxp3-deficient mice makes it difficult to analyze the roles of Tregs in humoral immunity of adult mice. In this study, we developed Foxp3 conditional-knockout mice (Foxp3floxR26CreERT2) in which the Foxp3 gene was inducibly deleted by tamoxifen administration. After oral administration of tamoxifen, titers of immunoglobulins, particularly IgG2c and IgE, were increased in Foxp3floxR26CreERT2 mice compared with that in controls. Under these conditions, CD4+ T cells from Foxp3floxR26CreERT2 mice had increased expression of several activation markers, including inducible costimulator and CD40 ligand, as well as the cytokines interleukin 4 and interferon gamma. In addition, the proportions of T follicular helper (Tfh) cells and germinal center (GC) B cells were increased in Foxp3floxR26CreERT2 mice compared with those in controls. These results indicated that Tregs controlled excessive or pathogenic antibody production by suppressing Tfh cell differentiation and GC formation. Furthermore, these data suggested that Foxp3floxR26CreERT2 mice could be a useful tool for screening therapeutic agents.
Agid:
6440679