• BMB Reports
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• 제55권2호
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• pp.57-64
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• 2022

Autoimmune disease is known to be caused by unregulated self-antigen-specific T cells, causing tissue damage. Although antigen specificity is an important mechanism of the adaptive immune system, antigen non-related T cells have been found in the inflamed tissues in various conditions. Bystander T cell activation refers to the activation of T cells without antigen recognition. During an immune response to a pathogen, bystander activation of self-reactive T cells via inflammatory mediators such as cytokines can trigger autoimmune diseases. Other antigen-specific T cells can also be bystander-activated to induce innate immune response resulting in autoimmune disease pathogenesis along with self-antigen-specific T cells. In this review, we summarize previous studies investigating bystander activation of various T cell types (NKT, γδ T cells, MAIT cells, conventional CD4⁺, and CD8⁺ T cells) and discuss the role of innate-like T cell response in autoimmune diseases. In addition, we also review previous findings of bystander T cell function in infection and cancer. A better understanding of bystander-activated T cells versus antigen-stimulated T cells provides a novel insight to control autoimmune disease pathogenesis.

• Molecules and Cells
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• 제44권5호
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• pp.328-334
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• 2021

The advent of the major histocompatibility complex (MHC) multimer technology has led to a breakthrough in the quantification and analysis of antigen-specific T cells. In particular, this technology has dramatically advanced the measurement and analysis of CD8 T cells and is being applied more widely. In addition, the scope of application of MHC multimer technology is gradually expanding to other T cells such as CD4 T cells, natural killer T cells, and mucosal-associated invariant T cells. MHC multimer technology acts by complementing the T-cell receptor-MHC/peptide complex affinity, which is relatively low compared to antigen-antibody affinity, through a multivalent interaction. The application of MHC multimer technology has expanded to include various functions such as quantification and analysis of antigen-specific T cells, cell sorting, depletion, stimulation to replace antigen-presenting cells, and single-cell classification through DNA barcodes. This review aims to provide the latest knowledge of MHC multimer technology, which is constantly evolving, broaden understanding of this technology, and promote its widespread use.

• 한국임상수의학회지
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• 제8권1호
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• pp.1-10
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• 1991

The B-lymphocyte differentiation from committed B-cell progenitors to antibody-secreting cells was discussed. B-cell progenitors derived from hematopoietic stem cells undergo the rearrangement of immunoglobulin(Ig) gene. The earliest cells as B-cell precursors have cytoplasmic Is(${\mu}$ chain). The entire Is molecule is expressed on the surface after synthesis of L chain. The resting B cells(Go stage) stimulated by binding antigen via Ig-receptors are activated(G$_1$ stage) and followed by proliferation(S stage), coupled with further selection(affinity maturation. class switch). The production of antibody against a particular antigen depends on the activation of B cells with surface Is capable of reacting with that antigen. This process does not occur in isolation but is controlled by helper and suppressor T cells and antigen presenting cells(APC). The mechanism of T cell-dependent B-cell response for production of antibody is largely explained by the cell to cell cooperation and soluble helper factors of T cells. 1) The antigen specific B cells and helper T cells are linked by Is-receptors, leading to the delivery of helper signals to the B cells. 2) Helper T cells recognize the processed antigen-derived peptides with the MHC class II molecules(la antigen) and is stimulated to secrete B-cell proliferation and differentiation factors which activate B cells of different antigenic specificity. The two models are shown currently 1) At low antigen concentration, only the antigen-specific B cell binds antigen and presents antigen-derived peptides with la molecules to helper T cells, which are stimulated to secrete cytokines(IL-4, IL-5, etc.) and 2) At high antigen concentration, antigen-derived peptides are presented by specific B cells, by B cells that endocytose the antigens, as well as by APC Cytokines secreted from helper T cells also lead to the activation of B cells and even bystander B cells in the on- vironmment and differentiate them into antibody-secreting plasma cells.

• Journal of Microbiology and Biotechnology
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• 제17권12호
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• pp.1955-1964
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• 2007

A recent report showed that analysis of CD154 expression in the presence of the secretion inhibitor Brefeldin A (Bref A) could be used to assess the entire repertoire of antigen-specific $CD4^+\;T$ helper cells. However, the capacity of intracellular CD154 expression to identify antigen-specific $CD8^+\;T$ cells has yet to be investigated. In this study, we compared the ability of intracellular CD154 expression to assess antigen-specific $CD8^+\;T$ cells with that of accepted standard assays, namely intracellular cytokine IFN-${\gamma}$ staining (ICS) and MHC class I tetramer staining. The detection of intracellular CD154 molecules in the presence of Bref A reflected the kinetic trend of antigen-specific $CD8^+\;T$ cell number, but unfortunately showed less sensitivity than ICS and tetramer staining. However, ICS levels peaked and saturated 8 h after antigenic stimulation in the presence of Bref A and then declined, whereas intracellular CD154 expression peaked by 8 h and maintained the saturated level up to 24 h post-stimulation. Moreover, intracellular CD154 expression in antigen-specific $CD8^+\;T$ cells developed in the absence of $CD4^+\;T$ cells changed little, whereas the number of IFN-${\gamma}$-producing $CD8^+\;T$ cells decreased abruptly. These results suggest that intracellular CD154 could aid the assessment of antigen-specific $CD8^+\;T$ cells, but does not have as much ability to identify heterogeneous $CD4^+\;T$ helper cells. Therefore, the combined analytical techniques of ICS and tetramer staining together with intracellular CD154 assays may be able to provide useful information on the accurate phenotype and functionality of antigen-specific $CD8^+\;T$ cells.

• Molecules and Cells
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• 제42권3호
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• pp.228-236
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• 2019

CD4 T cells differentiate into $ROR{\gamma}t/IL$-17A-expressing cells in the small intestine following colonization by segmented filamentous bacteria (SFB). However, it remains unclear whether SFB-specific CD4 T cells can differentiate directly from naïve precursors, and whether their effector differentiation is solely directed towards the Th17 lineage. In this study, we used adoptive T cell transfer experiments and showed that naïve CD4 T cells can migrate to the small intestinal lamina propria (sLP) and differentiate into effector T cells that synthesize IL-17A in response to SFB colonization. Using single cell RT-PCR analysis, we showed that the progenies of SFB responding T cells are not uniform but composed of transcriptionally divergent populations including Th1, Th17 and follicular helper T cells. We further confirmed this finding using in vitro culture of SFB specific intestinal CD4 T cells in the presence of cognate antigens, which also generated heterogeneous population with similar features. Collectively, these findings indicate that a single species of intestinal bacteria can generate a divergent population of antigen-specific effector CD4 T cells, rather than it provides a cytokine milieu for the development of a particular effector T cell subset.

• IMMUNE NETWORK
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• 제6권4호
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• pp.179-184
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• 2006

Background: Identification of antigen-specific T cells has yielded valuable information on pathologic process and the disease state. Assays for quantification of inflammatory cytokines or lytic-granule molecules have been generally used to evaluate antigen specific T cell response, however their applicability have been hampered due to the limited source of autologous antigen-presenting target cells (APC). Methods: K562, a leukemic cell line deficient of human leukocyte antigen (HLA), was transfected with a gene encoding HLA-A*02 (K562/ A*02) and its function as stimulator cells in inducing activation of HLA-matched T cells was evaluated by IFN-${\gamma}$ enzyme linked immunospot (ELISPOT) assay. Results: The stable transfectant K562/ A*02 pulsed with HLA- A*02 restricted peptide could specifically induce IFN-${\gamma}$ secretion by CD8+ T cells compared to no detectable secretion by CD4+ T cells. However, CD56+ NK cells secreted IFN-${\gamma}$ in both K562/ A*02 with peptide and without peptide. The number of IFN-${\gamma}$ secreted CD8+ T cells was increased according to the ratio of T cells to K562 and peptide concentration. Formalin-fixed K562/ A*02 showed similar antigen presenting function to live K562/ A*02. Moreover, K562/ A*02 could present antigenicpeptide to not only A*0201 restricted CD8+ T cells but also CD8+ T cells from A*0206 donor. Conclusion: These results suggest that K562/ A*02 could be generally used as target having specificity and negligible background for measuring CD8+ T cell responses and selective use of K562 with responsder matched HLA molecules on its surface as APC may circumvent the limitation of providing HLA-matched autologous target cells.

• 미생물학회지
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• 제47권4호
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• pp.342-347
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• 2011

인체의 바이러스 감염 방어기전에서 T 림프구는 중요한 역할을 한다. 하지만, 만성 C형 간염 바이러스의 일차적 복제장소인 간염 환자의 간에서 분리된 HCV 특이 T 림프구는 심각한 기능결핍을 보인다. 이러한 T 림프구 기능결핍의 이유로는 PD-1, CTLA-4 등 면역억제 물질의 발현, 또는 간에서 특이적으로 유도되는 면역내성(immune tolerance)이 있으나, 간세포(hepatocytes)와 HCV 특이 T 림프구의 상호작용에 대해서는 명확하게 확립되어 있지 않다. 따라서 본 연구에서는 HLA(human leukocyte antigen) A2+ 간암세포주(human hepatoma cell line; huh7.5)가 항원제시(antigen presentation)를 통해 효과적으로 HCV 특이 T 림프구를 활성화시키며 간암세포주(huh7.5) 표면의 PD-L (program death ligand) 1 발현은 T림프구의 활성을 감소시켜 면역조절의 가능성이 있음을 시사하였다. 또한, HCV 특이 tetramer 반응은 T 림프구의 과도한 활성으로 자기사멸(apoptosis)의 경로에 있음을 caspase 3 활성으로 확인하였고, 역시 PD-L1의 발현이 T 림프구를 자기사멸(apoptosis)로부터 구제하여 caspase 3 활성이 감소하는 것을 확인하였다. 이는 PD-L1과 간성(liver) T 림프구 표면의 PD-1 결합이 T 림프구의 자기사멸을 막고, 또한 그 기능을 회복시켜 만성 C형 간염 치료에 응용될 수 있음을 시사한다.

• 한국미생물생명공학회:학술대회논문집
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• 한국미생물생명공학회 2003년도 2003 Annual Meeting, BioExhibition and International Symposium
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• pp.55-62
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• 2003

The mucosal immune system provides a first line of defense against invasion of infectious agents via inhalation, ingestion and sexual contact. For the induction of protective immunity at these invasion sites, one must consider the use of the CMIS, which interconnects inductive tissues, including PP and NALT, and effector tissues of the intestinal, respiratory and genitourinary tracts. In order for the CMIS to induce maximal protective mucosal immunity, co-administration of mucosal adjuvant or use of mucosal antigen delivery vehicle has been shown to be essential. When vaccine antigen is administered via oral or nasal route, antigen-specific Th 1 and Th2 cells, cytotoxic T lymphocytes(CTLs) and IgA B cell responses are effectively induced by the CMIS. In the early stages of induction of mucosal immune response, the uptake of orally or nasally administered antigens is achieved through a unique set of antigen-sampling cells, M cells located in follicle-associated epithelium(FAE) of inductive sites. After successful uptake, the antigens are immediately processed and presented by the underlying DCs for the generation of antigen-specific T cells and IgA committed B cells. These antigen-specific lymphocytes are then home to the distant mucosal effector tissues for the induction of antigen-specific humoral(e.g., IgA) and cell-mediated (e.g., CTL and Th1) immune responses in order to form the first line of defense. Elucidation of the molecular/cellular characteristics of the immunological sequence of mucosal immune response beginning from the antigen sampling and processing/presentation by M cells and mucosal DCs followed by the effector phase with antigen-specific lymphocytes will greatly facilitate the design of a new generation of effective mucosal antigen-specific lymphocytes will greatly facilitate the design of a new generation of a new generation of effective mucosal adjuvants and of a vaccine deliver vehicle that maximizes the use of the CMIS.

• IMMUNE NETWORK
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• 제16권2호
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• pp.134-139
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• 2016

Programmed death-1 (PD-1) is a strong negative regulator of T lymphocytes in tumor-microenvironment. By engaging PD-1 ligand (PD-L1) on tumor cells, PD-1 on T cell surface inhibits anti-tumor reactivity of tumor-infiltrating T cells. Systemic blockade of PD-1 function using blocking antibodies has shown significant therapeutic efficacy in clinical trials. However, approximately 10 to 15% of treated patients exhibited serious autoimmune responses due to the activation of self-reactive lymphocytes. To achieve selective activation of tumor-specific T cells, we generated T cells expressing a dominant-negative deletion mutant of PD-1 (PD-1 decoy) via retroviral transduction. PD-1 decoy increased IFN-γ secretion of antigen-specific T cells in response to tumor cells expressing the cognate antigen. Adoptive transfer of PD-1 decoy-expressing T cells into tumor-bearing mice potentiated T cell-mediated tumor regression. Thus, T cell-specific blockade of PD-1 could be a useful strategy for enhancing both efficacy and safety of anti-tumor T cell therapy.

• Journal of Periodontal and Implant Science
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• 제44권5호
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• pp.235-241
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• 2014

Purpose: Regulatory T cells (Tregs), expressing CD4 and CD25 as well as Foxp3, are known to play a pivotal role in immunoregulatory function in autoimmune diseases, cancers, and graft rejection. Dendritic cells (DCs) are considered the major antigen-presenting cells (APCs) for initiating these T-cell immune responses, of which $CD103^+$ DCs are derived from precursor human peripheral blood mononuclear cells (PBMCs). The aim of the present study was to evaluate the capacity of these PBMC-derived $CD103^+$ DCs to promote the differentiation of antigen-specific Tregs. Methods: Monocyte-derived DCs were induced from $CD14^+$ monocytes from the PBMCs of 10 healthy subjects. Once the $CD103^+$ DCs were purified, the cell population was enriched by adding retinoic acid (RA). Peptide numbers 14 and 19 of Porphyromonas gingivalis heat shock protein 60 (HSP60) were synthesized to pulse $CD103^+$ DCs as a tool for presenting the peptide antigens to stimulate $CD3^+$ T cells that were isolated from human PBMC. Exogenous interleukin 2 was added as a coculture supplement. The antigen-specific T-cell lines established were phenotypically identified for their expression of CD4, CD25, or Foxp3. Results: When PBMCs were used as APCs, they demonstrated only a marginal capacity to stimulate peptide-specific Tregs, whereas $CD103^+$ DCs showed a potent antigen presenting capability to promote the peptide-specific Tregs, especially for peptide 14. RA enhanced the conversion of $CD103^+$ DCs, which paralleled the antigen-specific Treg-stimulating effect, though the differences failed to reach statistical significance. Conclusions: We demonstrated that $CD103^+$ DCs can promote antigen-specific Tregs from naive T cells, when used as APCs for an epitope peptide from P. gingivalis HSP60. RA was an effective reagent that induces mature DCs with the typical phenotypic expression of CD103 that demonstrated the functional capability to promote antigen-specific Tregs.