Abstract
Balance of Tfh/Tfr cell is critically important for the maintenance of immune tolerance, as evidenced by the fact that T follicular helper (Tfh) cells are central to the autoantibodies generation through providing necessary help for germinal center (GC) B cells, whereas T follicular regulatory (Tfr) cells significantly inhibit autoimmune inflammation process through restraining Tfh cell responses. However, signals underlying the regulation of Tfh and Tfr cells are largely undefined. Regulatory B cells (Bregs) is a heterogeneous subpopulation of B cells with immunosuppressive function. Considerable advances have been made in their functions to produce anti‐inflammatory cytokines and to regulate Th17, Th1, and Treg cells in autoimmune diseases. The recent identification of their correlations with dysregulated Tfr/Tfh cells and autoantibody production makes Bregs an important checkpoint in GC response. Bregs exert profound impacts on the differentiation, function, and distribution of Tfh and Tfr cells in the immune microenvironment. Thus, unraveling mechanistic information on Tfh-Breg and Tfr-Breg interactions will inspire novel implications for the establishment of homeostasis and prevention of autoantibodies in diverse diseases. This review summarizes the dysregulation of Tfh/Tfr cells in autoimmune diseases with a focus on the emerging role of Bregs in regulating the balance between Tfh and Tfr cells. The previously unsuspected crosstalk between Bregs and Tfh/Tfr cells will be beneficial to understand the cellular mechanisms of autoantibody production and evoke a revolution in immunotherapy for autoimmune diseases.
Highlights
Autoimmune disorders encompass a heterogeneous group of diseases in which immune tolerance is broken and the selfimmune system mistakenly attack autologous tissues, leading to local and/or systemic damage
This is supported by the fact that mice with aryl-hydrocarbon receptor (AhR) deletion developed exacerbated arthritis accompanied by reduced interleukin 10 (IL-10)-producing CD19+CD21hiCD24hiBregs [80]
Elucidating the cellular and molecular mechanisms underlying the activities of T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in the germinal center (GC) response as well as predominant determinants of the Tfr/Tfh balance will contribute to the regulation of autoantibody production
Summary
Autoimmune disorders encompass a heterogeneous group of diseases in which immune tolerance is broken and the selfimmune system mistakenly attack autologous tissues, leading to local and/or systemic damage. The well-established functions of B cells in immune responses are antibody production, pro-inflammatory cytokine secretion and antigen presentation It was not until the 1970s, that the existence of suppressive subsets of B cells was first confirmed in delayed hypersensitivity reactions [20]. Immunological advance further suggests the regulatory potential of Bregs on Tfr and Tfh cells in the germinal response [26, 33, 35, 36], providing new implications for understanding the production of autoantibodies in autoimmune diseases. We discuss the therapeutic implications based on Breg-mediated regulation of Tfh/Tfr cells in autoimmune diseases and propose several problems that needed to be solved regarding this therapy. This will give rise to more effective therapies and monitors for autoimmune disorders
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