• IMMUNE NETWORK
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• 제11권6호
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• pp.336-341
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• 2011

T cell receptor (TCR) signaling plays a critical role in T cell development, survival and differentiation. In the thymus, quantitative and/or qualitative differences in TCR signaling determine the fate of developing thymocytes and lead to positive and negative selection. Recently, it has been suggested that self-reactive T cells, escape from negative selection, should be suppressed in the periphery by regulatory T cells (Tregs) expressing Foxp3 transcription factor. Foxp3 is a master factor that is critical for not only development and survival but also suppressive activity of Treg. However, signals that determine Treg fate are not completely understood. The availability of mutant mice which harbor mutations in TCR signaling mediators will certainly allow to delineate signaling events that control intrathymic (natural) Treg (nTreg) development. Thus, we summarize the recent progress on the role of TCR signaling cascade components in nTreg development from the studies with murine model.

• BMB Reports
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• 제38권3호
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• pp.334-342
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• 2005

Recently, the existence of T cells with dual T cell receptor (TCR) in the immune system is generally accepted, while it has been controversial whether signals through one TCR would affect the functions of the other. In this study T cells expressing two different TCR were obtained from cross-hybrids of LCMV and AND TCR transgenic mice specific for the gp33 and peptide fragment of PCC (fPCC), respectively. Peptide stimulation demonstrated that the dual TCR T cells functioned independently in an antigen-specific manner. To examine whether the tolerance targeted for the one TCR affects the responsiveness of the other, the cross-hybrids were treated with gp33. Although T cells from F1 mice were rendered anergenic to gp33, no functional changes to fPCC were observed in terms of cellular proliferation and IL-2 secretion, suggesting that the dual TCR T cells remained reactive to fPCC. We therefore propose that signaling through the TCR is receptor-specific and 'negative dominance' of one TCR by tolerance induction is not applicable in this dual TCR system.

• IMMUNE NETWORK
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• 제23권5호
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• pp.37.1-37.11
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• 2023

Forkhead box P3-positive (Foxp3⁺)-inducible Tregs (iTregs) are readily generated by TGF-β1 at low TCR signaling intensity. TGF-β1-mediated Foxp3 expression is further enhanced by retinoic acid (RA) and lactoferrin (LF). However, the intensity of TCR signaling required for induction of Foxp3 expression by TGF-β1 in combination with RA and LF is unknown. Here, we found that either RA or LF alone decreased TGF-β1-mediated Foxp3 expression at low TCR signaling intensity. In contrast, at high TCR signaling intensity, the addition of either RA or LF strongly increased TGF-β1-mediated Foxp3 expression. Moreover, decreased CD28 stimulation was more favorable for TGF-β1/LF-mediated Foxp3 expression. Lastly, we found that at high signaling intensities of both TCR and CD28, combined treatment with TGF-β1, RA, and LF induced robust expression of Foxp3, in parallel with powerful suppressive activity against responder T cell proliferation. Our findings that TGFβ/RA/LF strongly generate high affinity Ag-specific iTreg population would be useful for the control of unwanted hypersensitive immune reactions such as various autoimmune diseases.

• IMMUNE NETWORK
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• 제2권2호
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• pp.72-78
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• 2002

Background: The precise mechanism by which CTLA-4 regulates T cell immune responses is still not fully understood. Previously we proposed that CTLA-4 could downregulate T cell function by modulating a signaling cascade initiated from the T cell receptor complex. The evidence for this notion comes from our findings that CTLA-4 associated with the T cell receptor zeta (TCR zeta) chain, and hence regulated TCR zeta phosphorylation by co-associated SHP-2 tyrosine phosphatase (1). In this report, we investigated whether any other signaling molecules could be involved in the CTLA-4 signaling pathway. Methods: We have taken biochemical approaches, such as immunoprecipitation followed by autoradiography or immunoblotting, to identify the molecules associated with CTLA-4. To perform these assays, we used activated primary T cells and ectopically transfected 293 cells. Various truncation mutants of CTLA-4 were used to map the interaction site on CTLA-4. Results: We found that in addition to TCR zeta and SHP-2, a recently cloned small adaptor molecule, SAP (SLAM-associated protein), was also able to associate with CTLA-4. We identified the domain of SAP association in CTLA-4 being a motif involving GVYVKM. This motif has been previously found to bind SHP-2 through its phosphorylated tyrosine interaction with SH-2 domain of SHP-2. Indeed, co-expression of SAP and SHP-2 reduced their binding to CTLA-4 significantly, suggesting that SAP and SHP-2 compete for the common binding site, GVYVKM. Thus, by blocking SHP-2 recruitment SAP could function as a negative regulator of CTLA-4. Conclusion: Taken together, our data suggest the existence of complicate signaling cascade in regulating CTLA-4 function, and further provide evidence that SAP can act either as a positive or negative regulator depending on the nature of the associating receptors.

• 한국산학기술학회논문지
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• 제20권9호
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• pp.211-226
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• 2019

백혈구 공통 항원인 돼지 CD45는 PTPRC 유전자에 암호화 되어 있으며, CD45엑손의 선택적 스플라이싱에 따라 다른 T-세포에서 발현되는 티로신 인산분해효소이다. CD45는 기질인 TCR의 $CD3{\zeta}$ 사슬, Lck, Fyn, Zap-70 kinase의 인산화된 티로신에서 인산을 분해하여 T-세포 항원 수용체(TCR) 매개 신호전달을 조절한다. CD45의 조절이상은 많은 면역 질환과 관련이 있어서, CD45는 면역약물 개발에 표적이 되어왔다. TCR 신호전달의 조절효과를 가진 주요 구조적 특징을 특성화하기 위해, 사람의 알려진 CD45 구조를 템플릿으로 적용하여 돼지 CD45RO(가장 작은 CD45 isoform)의 단백질 구조와 예측된 돼지 CD45RO 모델구조에 $CD3{\zeta}$ 사슬의 ITAM(REEpYDV)를 도킹하여 CD45RO/ITAM 펩타이드 결합구조를 예측하였다. 돼지 CD45RO의 구조적 특징은 세포외영역의 구조견고성과 세포질 내 티로신 인산분해효소 도메인의 KNRY와 PTP signature 기능모티프(두 기능 모티프는 ITAM 펩타이드 결합부위의 좁은 입구로 역할)에 있었다. 주요 구조특성은 돼지 CD45RO-ITAM 펩타이드 결합구조 안정성과 결합친화력을 조절하면서 기질 선택성에 영향을 준다. 돼지 CD45RO의 구조적 특성은 T-세포에 특이적인 면역 조절제를 탐색하는 데에 적용될 것이다.

• IMMUNE NETWORK
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• 제13권5호
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• pp.184-193
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• 2013

Co-signaling molecules are surface glycoproteins that positively or negatively regulate the T cell response to antigen. Co-signaling ligands and receptors crosstalk between the surfaces of antigen-presenting cells (APCs) and T cells, and modulate the ultimate magnitude and quality of T cell receptor (TCR) signaling. In the past 10 years, the field of co-signaling research has been advanced by the understanding of underlying mechanisms of the immune modulation led by newly identified co-signaling molecules and the successful preclinical and clinical trials targeting co-inhibitory molecules called immune checkpoints in the treatment of autoimmune diseases and cancers. In this review, we briefly describe the characteristics of well-known B7 co-signaling family members regarding the expression, functions and therapeutic implications and to introduce newly identified B7 members such as B7-H5, B7-H6, and B7-H7.

• Journal of Ginseng Research
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• 제19권2호
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• pp.117-121
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• 1995

We studied the effects of ginsenoside-$Rg_1$ (G-$Rg_1$) extracted from Panax ginseng C.A. Meyer on $p56^{kk}$ kinase and cell proliferation in Jurkat T cells. $p56^{kk}$ was maximally activated within 5 min after the treatment of 16.7 $\mu\textrm{g}$/ml of G-$Rg_1$ increasing the activity by 1.2-2 times relative to untreated control, thereafter its activity was gradually decreased to the level of untreated control. The action of EGTA on the kinase was altered by the addition of G-$Rg_1$, accompanying the band shift of $p56^{kk}$ to $p60^{kk}$. In addition, G-$Rg_1$promoted cell proliferation in a concentration-dependent manner. These results suggest that G-$Rg_1$ may be involved in T cell receptor-CD3 (TCR) signaling via the activation of $p56^{kk}$ and the chance of cellular calcium concentration.

• IMMUNE NETWORK
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• 제9권2호
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• pp.53-57
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• 2009

Engagement of the immunoreceptors initiates signaling cascades resulting in lymphocyte activation and differentiation to effector cells, which are essential for the elimination of pathogens from the body. For the transduction of these immunoreceptor-mediated signals, several linker proteins termed transmembrane adaptor proteins (TRAPs) were shown to be required. TRAPs serve as platforms for the assembly and membrane targeting of the specific signaling proteins. Among seven TRAPs identified so far, LAT and LIME were shown to act as a positive regulator in TCR-mediated signaling pathways. In this review, we will discuss the functions of LAT and LIME in modulating T cell development, activation and differentiation.

• Molecules and Cells
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• 제20권3호
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• pp.339-347
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• 2005

IL-17 (IL-17A or CTLA-8) is the founding member of a novel family of inflammatory cytokines, and emerging evidence indicates that it plays a central role in inflammation and autoimmunity. IL-17 is made primarily, if not exclusively by T cells, but relatively little is known about how its expression is regulated. In the present study, we examined the requirements and mechanisms for IL-17 expression in primary mouse lymphocytes. Like many cytokines, IL-17 is induced rapidly in primary T cells after stimulation of the T cell receptor (TCR) through CD3 crossinking. Surprisingly, however, the pattern of regulation of IL-17 is different in mice than in humans, because "costimulation" of T cells through CD28 only mildly enhanced IL-17 expression, whereas levels of IL-2 were dramatically enhanced. Similarly, several other costimulatory molecules such as ICOS, 4-1BB and CD40L exerted only very weak enhancing effects on IL-17 production. In agreement with other reports, IL-23 enhanced CD3-induced IL-17 expression. However, IL-17 production can occur autonomously in T cells, as neither dendritic cells nor IL-23 were necessary for promoting short-term production of IL-17. Finally, to begin to characterize the TCR-mediated signaling pathway(s) required for IL-17 production, we showed that IL-17 expression is sensitive to cyclosporin-A and MAPK inhibitors, suggesting the involvement of the calcineurin/NFAT and MAPK signaling pathways.

• 농업과학연구
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• 제47권2호
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• pp.361-373
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• 2020

Integrins such as lymphocyte function-associated antigen -1 (LFA-1) have an essential role in T cell immunity. Integrin activation, namely, the transition from the inactive conformation to the active one, takes place when an intracellular signal is generated by specific receptors such as T cell receptors (TCRs) and chemokine receptors in T cells. In an effort to explore the molecular mechanisms underlying the TCR-mediated LFA-1 activation, we had previously established a high-throughput cell-based assay and screened a chemical library deposited in the National Institute of Health in the United States. As a result, several hits had been isolated including HIKS-1 (Benzo[b]thiophene-3-carboxylic acid, 2-[3-[(2-carboxyphenyl) thio]-2,5-dioxo-1-pyrrolinyl]-4,5,6,7-tetrahydro-,3-ethyl ester). In an attempt to reveal the mode of action of HIKS-1, in this study, we did drug affinity responsive target stability (DARTS) assay finding that HIKS-1 interacted with the IQ motif containing GTPase activating protein 1 (IQGAP1), a 189 kDa multidomain scaffold protein critically involved in various signaling mechanisms. Furthermore, the cellular thermal shift assay (CETSA) provided compelling evidence that HIKS-1 also interacted with IQGAP1 in vivo. Taken together, it can be concluded that HIKS-1 interferes with the TCR-mediated LFA-1 activation by interacting with IQGAP1 and thereby disrupting the signaling pathway for LFA-1 activation.