• Biomolecules & Therapeutics
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• v.24 no.3
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• pp.244-251
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• 2016

Understanding the developmental mechanisms of humoral immunity against intranasal antigens is essential for the development of therapeutic approaches against air-borne pathogens as well as allergen-induced pulmonary inflammation. Follicular helper T (Tfh) cells expressing CXCR5 are required for humoral immunity by providing IL-21 and ICOS costimulation to activated B cells. However, the regulation of Tfh cell responses against intranasal antigens remains unclear. Here, we found that the generation of Tfh cells and germinal center B cells in the bronchial lymph node against intranasal proteinase antigens was independent of $TGF-{\beta}$. In contrast, administration of STAT3 inhibitor STA-21 suppressed the generation of Tfh cells and germinal center B cells. Compared with wild-type OT-II T cells, STAT3-deficient OT-II T cells transferred into recipients lacking T cells not only showed significantly reduced frequency Tfh cells, but also induced diminished IgG as well as IgE specific for the intranasal antigens. Cotransfer study of wild-type OT-II and STAT3-deficient OT-II T cells revealed that the latter failed to differentiate into Tfh cells. These findings demonstrate that T cell-intrinsic STAT3 is required for the generation of Tfh cells to intranasal antigens and that targeting STAT3 might be an effective approach to ameliorate antibody-mediated pathology in the lung.

• IMMUNE NETWORK
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• v.16 no.4
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• pp.219-232
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• 2016

Production of high affinity antibodies for antigens is a critical component for the immune system to fight off infectious pathogens. However, it could be detrimental to our body when the antigens that B cells recognize are of self-origin. Follicular helper T, or Tfh, cells are required for the generation of germinal center reactions, where high affinity antibody-producing B cells and memory B cells predominantly develop. As such, Tfh cells are considered as targets to prevent B cells from producing high affinity antibodies against self-antigens, when high affinity autoantibodies are responsible for immunopathologies in autoimmune disorders. This review article provides an overview of current understanding of Tfh cells and discusses it in the context of animal models of autoimmune diseases and allograft rejections for generation of novel therapeutic interventions.

• IMMUNE NETWORK
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• v.24 no.1
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• pp.8.1-8.17
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• 2024

Follicular helper T cells (Tfh) play a crucial role in generating high-affinity antibodies (Abs) and establishing immunological memory. Cytokines, among other functional molecules produced by Tfh, are central to germinal center (GC) reactions. This review focuses on the role of cytokines, including IL-21 and IL-4, in regulating B cell responses within the GC, such as differentiation, affinity maturation, and plasma cell development. Additionally, this review explores the impact of other cytokines like CXCL13, IL-10, IL-9, and IL-2 on GC responses and their potential involvement in autoimmune diseases, allergies, and cancer. This review highlights contributions of Tfh-derived cytokines to both protective immunity and immunopathology across a spectrum of diseases. A deeper understanding of Tfh cytokine biology holds promise for insights into biomedical conditions.

• IMMUNE NETWORK
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• v.14 no.5
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• pp.227-236
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• 2014

Understanding germinal center reactions is crucial not only for the design of effective vaccines against infectious agents and malignant cells but also for the development of therapeutic intervention for the treatment of antibody-mediated immune disorders. Recent advances in this field have revealed specialized subsets of T cells necessary for the control of B cell responses in the follicle. These cells include follicular regulatory T cells and Qa-1-restricted cluster of differentiation $(CD)8^+$ regulatory T cells. In this review, we discuss the current knowledge related to the role of regulatory T cells in the B cell follicle.

• Biomolecules & Therapeutics
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• v.25 no.2
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• pp.130-139
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• 2017

$CXCR5^+$ T follicular helper (Tfh) cells are associated with aberrant autoantibody production in patients with antibody-mediated autoimmune diseases including lupus. Follicular regulatory T (Tfr) cells expressing CXCR5 and Bcl6 have been recently identified as a specialized subset of $Foxp3^+$ regulatory T (Treg) cells that control germinal center reactions. In this study, we show that retroviral transduction of CXCR5 gene in $Foxp3^+$ Treg cells induced a stable expression of functional CXCR5 on their surface. The Cxcr5-transduced Treg cells maintained the expression of Treg cell signature genes and the suppressive activity. The expression of CXCR5 as well as Foxp3 in the transduced Treg cells appeared to be stable in vivo in an adoptive transfer experiment. Moreover, Cxcr5-transduced Treg cells preferentially migrated toward the CXCL13 gradient, leading to an effective suppression of antibody production from B cells stimulated with Tfh cells. Therefore, our results demonstrate that enforced expression of CXCR5 onto Treg cells efficiently induces Tfr cell-like properties, which might be a promising cellular therapeutic approach for the treatment of antibody-mediated autoimmune diseases.

• BMB Reports
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• v.51 no.8
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• pp.371-372
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• 2018

Cardiovascular disease such as atherosclerosis is caused by imbalanced lipid metabolism and represents a leading cause of death worldwide. Epidemiological studies show that patients with systemic autoimmune diseases exhibit a higher incidence of atherosclerosis. Conversely, hyperlipidemia has been known to accelerate the incidence of autoimmune diseases in humans and in animal models. However, there is a considerable gap in our understanding of how atherosclerosis impacts the development of the autoimmunity in humans, and vice versa. The atherosclerosis-related autoimmune diseases include psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE) and diabetes mellitus. By using animal models of atherosclerosis and SLE, we have recently demonstrated that hyperlipidemia significantly accelerates the development of autoantibodies, by inducing autoimmune follicular helper T ($T_{FH}$) cells. Mechanistic studies have identified that hyperlipidemia induces IL-27 production in a TLR4-dependent manner, likely via downregulating LXR expression in dendritic cells. In this case, mice lacking IL-27 do not develop enhanced antibody responses. Thus it is noted that these findings propose a mechanistic insight responsible for the tight association between cardiovascular diseases and SLE in humans.

• IMMUNE NETWORK
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• v.1 no.1
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• pp.26-31
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• 2001

Background : Follicular dendritic cells (FDCs) play key roles during T cell-dependent humoral immune responses by allowing antigen-specific B cells to survive, proliferate, and differentiate within the FDC networks of secondary follicles, i.e., germinal centers (GC). Methods: A novel monoclonal antibody, 3C8, was generated by immunizing with an FDC line HK, in order to understand the molecular signals involved in the FDC-B cell interactions in the microenvironment of the GC. Results: The 3C8 antibody did not bind to mononuclear cells, including T cells, B cells, and monocytes. Murine L929 and human skin fibroblasts exhibited no or little reactivity to 3C8. However, 3C8 specifically recognized HK cells by flowcytometry. Furthermore, the antigen recognized by 3C8 was restricted to the GC of the human tonsil. Dendritic networks of the GC were intensely stained by 3C8, but cells outside the GC were not. Conclusion: Our results suggest that the antigen 3C8 may play some unique role on FDCs during the GC reactions.

• IMMUNE NETWORK
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• v.20 no.5
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• pp.42.1-42.10
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• 2020

Long-lasting post-switched plasma cells (PCs) arise mainly from germinal center (GC) reactions, but little is known about the mechanism by which GC B cells differentiate into PCs. Based on our observation that the expression of the transcription factor CCAAT/enhancer binding protein β (C/EPBβ) is associated with the emergence of post-switched PCs, we enquired whether a cell-autonomous function of C/EPBβ is involved in the program for PC development. To address this, we generated C/EPBβ-deficient mice in which the Cebpb locus was specifically deleted in B cells after transcription of the Ig γ1 constant gene segment (Cγ1). In response to in vitro stimulation, B cells from these Cebpb^fl/flCγ1^Cre/+ mice had defects in the induction of B lymphocyte-induced maturation protein 1 (Blimp1) and the formation of IgG1⁺ PCs, but not in proliferation and survival. At steady state, the Cebpb^fl/flCγ1^Cre/+ mice had reduced serum IgG1 titers but normal IgG2c and IgM titers. Moreover, upon immunization with T-dependent Ag, the mice produced reduced levels of Ag-specific IgG1 Ab, and were defective in the production of Ag-specific IgG1 Ab-secreting cells. These results suggest that a cell-autonomous function of C/EPBβ is crucial for differentiation of post-switched GC B cells into PCs through a Blimp1-dependent pathway.