• IMMUNE NETWORK
• /
• 제24권1호
• /
• pp.8.1-8.17
• /
• 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.

• Biomolecules & Therapeutics
• /
• 제25권2호
• /
• pp.130-139
• /
• 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.

• IMMUNE NETWORK
• /
• 제12권6호
• /
• pp.230-239
• /
• 2012

Activation-induced cytidine deaminase (AID) is an enzyme that is predominantly expressed in germinal center B cells and plays a pivotal role in immunoglobulin class switch recombination and somatic hypermutation for antibody (Ab) maturation. These two genetic processes endow Abs with protective functions against a multitude of antigens (pathogens) during humoral immune responses. In B cells, AID expression is regulated at the level of either transcriptional activation on AID gene loci or post-transcriptional suppression of AID mRNA. Furthermore, AID stabilization and targeting are determined by post-translational modifications and interactions with other cellular/nuclear factors. On the other hand, aberrant expression of AID causes B cell leukemias and lymphomas, including Burkitt's lymphoma caused by c-myc/IgH translocation. AID is also ectopically expressed in T cells and non-immune cells, and triggers point mutations in relevant DNA loci, resulting in tumorigenesis. Here, I review the recent literatures on the function of AID, regulation of AID expression, stability and targeting in B cells, and AID-related tumor formation.

• IMMUNE NETWORK
• /
• 제14권1호
• /
• pp.21-29
• /
• 2014

Follicular helper T ($T_{FH}$) cells are recently highlighted as their crucial role for humoral immunity to infection as well as their abnormal control to induce autoimmune disease. During an infection, na$\ddot{i}$ve T cells are differentiating into $T_{FH}$ cells which mediate memory B cells and long-lived plasma cells in germinal center (GC). $T_{FH}$ cells are characterized by their expression of master regulator, Bcl-6, and chemokine receptor, CXCR5, which are essential for the migration of T cells into the B cell follicle. Within the follicle, crosstalk occurs between B cells and $T_{FH}$ cells, leading to class switch recombination and affinity maturation. Various signaling molecules, including cytokines, surface molecules, and transcription factors are involved in $T_{FH}$ cell differentiation. IL-6 and IL-21 cytokine-mediated STAT signaling pathways, including STAT1 and STAT3, are crucial for inducing Bcl-6 expression and $T_{FH}$ cell differentiation. $T_{FH}$ cells express important surface molecules such as ICOS, PD-1, IL-21, BTLA, SAP and CD40L for mediating the interaction between T and B cells. Recently, two types of microRNA (miRNA) were found to be involved in the regulation of $T_{FH}$ cells. The miR-17-92 cluster induces Bcl-6 and $T_{FH}$ cell differentiation, whereas miR-10a negatively regulates Bcl-6 expression in T cells. In addition, follicular regulatory T ($T_{FR}$) cells are studied as thymus-derived $CXCR5^+PD-1^+Foxp3^+\;T_{reg}$ cells that play a significant role in limiting the GC response. Regulation of $T_{FH}$ cell differentiation and the GC reaction via miRNA and $T_{FR}$ cells could be important regulatory mechanisms for maintaining immune tolerance and preventing autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we review recent studies on the various factors that affect $T_{FH}$ cell differentiation, and the role of $T_{FH}$ cells in autoimmune diseases.

• IMMUNE NETWORK
• /
• 제22권6호
• /
• pp.50.1-50.19
• /
• 2022

Autoreactive B cells are not entirely deleted, but some remain as immunocompetent or anergic B cells. Although the persistence of autoreactive B cells as anergic cells has been shown in transgenic mouse models with the expression of B cell receptor (BCR) reactive to engineered self-antigen, the characterization of naturally occurring anergic B cells is important to identify them and understand their contribution to immune regulation or autoimmune diseases. We report here that a low-level expression of CD138 in the splenic B cells marks naturally arising anergic B cells, not plasma cells. The CD138^int B cells consisted of IgM^lowIgD^high follicular (FO) B cells and transitional 3 B cells in homeostatic conditions. The CD138^int FO B cells showed an anergic gene expression profile shared with that of monoclonal anergic B cells expressing engineered BCRs and the gene expression profile was different from those of plasma cells, age-associated B cells, or germinal center B cells. The anergic state of the CD138^int FO B cells was confirmed by attenuated Ca²⁺ response and failure to upregulate CD69 upon BCR engagement with anti-IgM, anti-IgD, anti-Igκ, or anti-IgG. The BCR repertoire of the CD138^int FO B cells was distinct from that of the CD138^- FO B cells and included some class-switched B cells with low-level somatic mutations. These findings demonstrate the presence of polyclonal anergic B cells in the normal mice that are characterized by low-level expression of CD138, IgM downregulation, reduced Ca²⁺ and CD69 responses upon BCR engagement, and distinct BCR repertoire.

• 한국발생생물학회지:발생과생식
• /
• 제12권2호
• /
• pp.125-132
• /
• 2008

멜라토닌(N-acetyl-5-methoxytryptamine)은 포유동물의 뇌의 송과선에서 분비되는 호르몬으로 수면과 생체 리듬 등을 조절하고 난소 기능과 번식에도 영향을 미친다. 또한, 강력한 scavenger로서 항산화제의 역할을 한다. 이 연구의 목적은 멜라토닌이 생쥐 난구세포-핵낭(germinal vesicle, GV) 시기 난자 복합체의 체외성숙에 미치는 영향을 알아보는 것이다. 3주령의 ICR 암컷 생쥐의 난소에서 회수된 난자-난구세포 복합체를 0, 0.1 nM, 10 nM, 1,000 nM의 멜라토닌이 첨가된 배양액에서 18시간 동안 배양하고, 제1극체의 방출 여부를 확인하여 성숙율을 확인하였다. 체외성숙 후 TUNEL assay와 성숙율이 가장 높게 나타났다. 체외성숙된 난자에서는 세포자연사가 나타나지 않았으나 난구세포에서는 관찰되었으며, 1,000 nM을 첨가하여 배양한 군의 난구세포는 유의하게 낮은 세포자연사를 나타냈다. 그리고 1,000 nM의 멜라토닌을 첨가한 군의 난구세포에서 멜라토닌 수용체의 mRNA가 대조군에 비해 낮게 발현되었다. 이상의 결과를 종합하면 체외성숙 배양액에 첨가된 멜라토닌은 난구세포의 세포자연사를 줄여줌으로써 생쥐 미성숙 난자의 체외성숙을 향상시키는 역할을 하는 것으로 사료된다.

• International Journal of Stem Cells
• /
• 제15권3호
• /
• pp.291-300
• /
• 2022

Background and Objectives: Many preclinical studies have been conducted using animal disease models to determine the effectiveness of human mesenchymal stem cells (hMSCs) for treating immune and inflammatory diseases based on the belief that hMSCs are not immunogenic across species. However, several researchers have suggested xenogeneic immune responses to hMSCs in animals, still without detailed features. This study aimed to investigate a xenogeneic humoral immune response to hMSCs in mice in detail. Methods and Results: Balb/c mice were intraperitoneally injected with adipose tissue-derived or Wharton's jelly-derived hMSCs. Sera from these mice were titrated for each isotype. To confirm specificity of the antibodies, hMSCs were stained with the sera and subjected to a flow cytometic analysis. Spleens were immunostained for proliferating cell nuclear antigen to verify the germinal center formation. Additionally, splenocytes were subjected to a flow cytometric analysis for surface markers including GL-7, B220, CD4, CD8, CD44, and CD62L. Similar experiments were repeated in C57BL/6 mice. The results showed increased IgG₁ and IgG_2a titers in the sera from Balb/c mice injected with hMSCs, and the titers were much higher in the secondary sera than in the primary sera. These antibodies were specifically stained the hMSCs. Germinal centers were observed in the spleen, and flow cytometric analysis of the splenocytes showed higher frequencies of centroblasts (B220⁺ GL7⁺) and memory T cells (CD62L⁺ CD44⁺) both in CD4⁺ and CD8⁺ subsets. Similar results were obtained for C57BL/6 mice. Conclusions: hMSCs induced a humoral immune response in mice, with characters of T cell-dependent immunity.

• Biomolecules & Therapeutics
• /
• 제30권6호
• /
• pp.546-552
• /
• 2022

Epidermal cell adhesion molecule (EpCAM) is a tumor-associated antigen (TAA), which has been considered as a cancer vaccine candidate. The EpCAM protein fused to the fragment crystallizable region of immunoglobulin G (IgG) tagged with KDEL endoplasmic reticulum (ER) retention signal (EpCAM-FcK) has been successfully expressed in transgenic tobacco (Nicotiana tabacum cv. Xanthi) and purified from the plant leaf. In this study, we investigated the ability of the plant-derived EpCAM-FcK (EpCAM-FcK^P) to elicit an immune response in vivo. The animal group injected with the EpCAM-FcK^P showed a higher differentiated germinal center (GC) B cell population (~9%) compared with the animal group injected with the recombinant rhEpCAM-Fc chimera (EpCAM-Fc^M). The animal group injected with EpCAM-FcK^P (~42%) had more differentiated T follicular helper cells (Tfh) than the animal group injected with EpCAM-Fc^M (~7%). This study demonstrated that the plant-derived EpCAM-FcK fusion antigenic protein induced a humoral immune response in mice.

• IMMUNE NETWORK
• /
• 제20권5호
• /
• pp.42.1-42.10
• /
• 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.

• IMMUNE NETWORK
• /
• 제6권2호
• /
• pp.59-66
• /
• 2006

Background: CM1 (Centrocyte/-blast Marker I) defined by a mAb developed against concanavalin-A activated PBMC, is expressed specifically on a subpopulation of centroblasts and centrocytes of human germinal center (GC) B cells. Burkitt lymphoma (BL) is a tumor consisting of tumor cells with the characteristics of GC B cell. Previously we reported that CM1 ligation with anti-CM1 mAb induced apoptosis in Ramos $(IgM^{high})$ and Raji $(IgM^{low})$ cells. Methods & Results: In the present study, we observed that CM1 ligation with anti-CM1 mAb induced Fas ligand and Fas expression in Ramos cells, but not in Raji cells. Furthermore, anti-Fas blocking antibody, ZB4, blocked CM1-mediated apoptosis effectively in Ramos cells, but not in Raji cells. Increased mitochondrial membrane permeabilization, which was measured by $DiOC_6$, was observed only in Raji cells. In contrast to no significant change of Bax known as pro-apoptotic protein, anti-apoptotic protein Bcl-2 was significantly decreased in Raji cells. In addition, we observed that CM1 ligation increased release of mitochondrial cytochrome c and upregulated caspase-9 activity in Raji cells. Conclusion: These results suggest that apoptosis induced by CM1-ligation is mediated by Fas-Fas ligand interaction in Ramos cells, whereas apoptosis is mediated by down-regulation of Bcl-2 and subsequent decrease of mitochondrial membrane potential in Raji cells.