Proliferation of activated CD1d‐restricted NKT cells is down‐modulated by lymphocyte activation gene‐3 signaling via cell cycle arrest in S phase

Byun, Hyun Jung; Jung, Woon Won; Lee, Dong Sup; Kim, Sanghee; Kim, Sang Joon; Park, Chung Gyu; Chung, Hee Yong; Chun, Taehoon

doi:10.1016/j.cellbi.2006.11.002

Cited by 37 publications

(37 citation statements)

References 26 publications

(20 reference statements)

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“…LAG-3 is considered as an important receptor that provides a negative signal in activated T cells to regulate T cell homeostasis (3,(10)(11)(12)(13)(14). Identification of the mechanism that regulates molecular trafficking of LAG-3 may thus be essential to better understand T cell homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Later, LAG-3 expression has also been detected in other cells, including activated NK cells, invariant NKT cells, and B cells (2)(3)(4). LAG-3 is structurally similar to CD4; LAG-3 and CD4 contain four extracellular Ig-like domains with conserved structural resemblance, although they share ,20% amino acid sequence similarity (5).…”

mentioning

confidence: 99%

“…First, CD4 is constitutively expressed on T cells and invariant NKT cells, whereas LAG-3 expression is only observed in activated T cells and invariant NKT cells (1)(2)(3)(4)8). Second, LAG-3 has much higher binding affinity to MHC class II molecules than CD4 does (5,6).…”

mentioning

confidence: 99%

“…Second, LAG-3 has much higher binding affinity to MHC class II molecules than CD4 does (5,6). Third, LAG-3 mediates signaling with a negative regulatory effect on T cells and invariant NKT cells, whereas CD4 costimulates and amplifies TCR signaling to activate those cells (3,5,(9)(10)(11)(12). In particular, LAG-3 associates with the CD3/TCR complex present on the surface of activated T cells and downregulates the CD3/TCR activation signaling pathway (9).…”

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confidence: 99%

“…Additionally, cross-linking of LAG-3 or introduction of LAG-3 impairs CD4 + T cell activation, as determined by altered calcium fluxes, IL-2 expression, and a reduction in CD3/TCR complex expression (5,9). Moreover, the signaling mediated by LAG-3 inhibits the proliferation of T cells and invariant NKT cells (3,(10)(11)(12). Therefore, LAG-3 may play an important role in maintaining T cell homeostasis by transducing a negative signal to calm down the activated T cells.…”

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confidence: 99%

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Trafficking of LAG-3 to the Surface on Activated T Cells via Its Cytoplasmic Domain and Protein Kinase C Signaling

Bae

Lee

Park

et al. 2014

The Journal of Immunology

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Lymphocyte activation gene-3 (LAG-3; CD223), a structural homolog of CD4, binds to MHC class II molecules. Recent research indicated that signaling mediated by LAG-3 inhibits T cell proliferation, and LAG-3 serves as a key surface molecule for the function of regulatory T cells. Previous reports demonstrated that the majority of LAG-3 is retained in the intracellular compartments and is rapidly translocated to the cell surface upon stimulation. However, the mechanism by which LAG-3 translocates to the cell surface was unclear. In this study, we examined the trafficking of human LAG-3 under unstimulated as well as stimulated conditions of T cells. Under the unstimulated condition, the majority of LAG-3 did not reach the cell surface, but rather degraded within the lysosomal compartments. After stimulation, the majority of LAG-3 translocated to the cell surface without degradation in the lysosomal compartments. Results indicated that the cytoplasmic domain without Glu-Pro repetitive sequence is critical for the translocation of LAG-3 from lysosomal compartments to the cell surface. Moreover, protein kinase C signaling leads to the translocation of LAG-3 to the cell surface. However, two potential serine phosphorylation sites from the LAG-3 cytoplasmic domain are not involved in the translocation of LAG-3. These results clearly indicate that LAG-3 trafficking from lysosomal compartments to the cell surface is dependent on the cytoplasmic domain through protein kinase C signaling in activated T cells.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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Trafficking of LAG-3 to the Surface on Activated T Cells via Its Cytoplasmic Domain and Protein Kinase C Signaling

Bae

Lee

Park

et al. 2014

The Journal of Immunology

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Characterization of 405B8H3(D‐E), a newly engineered high affinity chimeric LAG‐3 antibody with potent antitumor activity

Lan

Yang²,

Wang³

et al. 2023

FEBS Open Bio

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Lymphocyte activation gene-3 (LAG-3) is a type I transmembrane protein with structural similarities to CD4. Overexpression of LAG-3 enables cancer cells to escape immune surveillance, while its blockade reinvigorates exhausted T cells and strengthens anti-infection immunity. Blockade of LAG-3 may have antitumor effects. Here, we generated a novel anti-LAG-3 chimeric antibody, 405B8H3(D-E), through hybridoma technology from monoclonal antibodies produced in mice. The heavy-chain variable region of the selected mouse antibody was grafted onto a human IgG4 scaffold, while a modified light-chain variable region was coupled to the human kappa light-chain constant region. 405B8H3(D-E) could effectively bind LAG-3-expressing HEK293 cells. Moreover, it could bind cynomolgus monkey (cyno) LAG-3 expressed on HEK293 cells with a higher affinity than the reference anti-LAG-3 antibody BMS-986016. Furthermore, 405B8H3(D-E) promoted interleukin-2 secretion and was able to block the interactions of LAG-3 with liver sinusoidal endothelial cell lectin and major histocompatibility complex II molecules. Finally, 405B8H3(D-E) combined with anti-mPD-1-antibody showed effective therapeutic potential in the MC38 tumor mouse model. Therefore, 405B8H3(D-E) is likely to be a promising candidate therapeutic antibody for immunotherapy. Triebel et al.[1] first discovered lymphocyte activation gene-3 (LAG-3) among molecules differentially expressed in interleukin-2 (IL-2)-dependent natural killer cells (NK). LAG-3 is composed of 525 amino acids, with four Ig-like domains, termed domain 1 (D1) to domain 4 (D4). The D1 region contains a proline-rich ring structure, which specifically binds to major histocompatibility complex II (MHC-II) molecules [2]. Like CD4, LAG-3 binds the MHC-II on antigen-presenting cells, but with a much stronger affinity, which effectively inhibit T-cell activation [2]. LAG-3 is expressed on CD4+ and CD8+ T cells,

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T cell exhaustion in cancer: Mechanisms and clinical implications

Wang

Huang

et al. 2018

J of Cellular Biochemistry

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During chronic viral infection or cancer, the immune system usually induces a corresponding immune response against pathogens or cancer cells so as to prevent worsening disease. T cell exhaustion in which reduced and dysfunctional effector T cells lead to immune escape is one of the mechanisms that pathogens or cancer cells get rid of control from the immune system. In this review, we discuss some mechanisms associated with T cell exhaustion and enumerate current methods of reversing T cell exhaustion. We also summarize current targeted treatment strategies and put forward following aspects that required to research.

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Proliferation of activated CD1d‐restricted NKT cells is down‐modulated by lymphocyte activation gene‐3 signaling via cell cycle arrest in S phase

Cited by 37 publications

References 26 publications

Trafficking of LAG-3 to the Surface on Activated T Cells via Its Cytoplasmic Domain and Protein Kinase C Signaling

Trafficking of LAG-3 to the Surface on Activated T Cells via Its Cytoplasmic Domain and Protein Kinase C Signaling

Characterization of 405B8H3(D‐E), a newly engineered high affinity chimeric LAG‐3 antibody with potent antitumor activity

T cell exhaustion in cancer: Mechanisms and clinical implications

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