Role of LAG-3 in Regulatory T Cells

Huang, Ching Tai; Workman, Creg J.; Flies, Dallas B.; Pan, Xiaoyu; Marson, Aimee L.; Zhou, Gang; Hipkiss, Edward L.; Ravi, Sowmya; Kowalski, Jeanne; Levitsky, Hyam I.; Powell, Jonathan D.; Pardoll, Drew M.; Drake, Charles G.; Vignali, Dario A.A.

doi:10.1016/j.immuni.2004.08.010

Cited by 1,090 publications

(917 citation statements)

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“…5B). In this model, the infiltration of CD4 + clonotypic T cells in the lungs is prominent at necropsy [27]. We performed histology on lung tissue on day 4 post T cell transfer (Fig.…”

Section: Increased Autoimmunity Induced By Egr-3 -/-Autoreactive T Cellsmentioning

confidence: 99%

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Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

et al. 2008

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TCR-induced NF-AT activation leads to the up-regulation of multiple genes involved in T cell anergy. Since NF-AT is also involved in T cell activation, we have endeavored to dissect TCR-induced activating and inhibitory genetic programs. This approach revealed roles for the early growth response (Egr) family of transcription factors and the Egr coactivator/corepressor NGFI-A-binding protein (NAB)2 in regulating T cell function. TCR-induced Egr-1 and NAB2 enhance T cell function, while Egr-2 and Egr-3 inhibit T cell function. In this report, we demonstrate that Egr-2 and Egr-3 are induced by NF-AT in the absence of AP-1, while Egr-1 and NAB2 both require AP-1-mediated transcription. Our data suggest that Egr-3 is upstream of Egr-2, and that mechanistically Egr-2 and Egr-3 suppress Egr-1 and NAB2 expression. Functionally, T cells from Egr-2 and Egr-3 null mice are hyperresponsive while T cells from Egr-3 transgenic, overexpressing mice are hyporesponsive. Furthermore, an in vivo model of autoimmune pneumonitis reveals that T cells from Egr-3 null mice hasten death while Egr-3-overexpressing T cells cause less disease. Overall, our data suggest that just as the Egr/NAB network of genes control cell fate in other systems, TCR-induced Egr-1, 2, 3 and NAB2 control the fate of antigen recognition in T cells.

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“…5B). In this model, the infiltration of CD4 + clonotypic T cells in the lungs is prominent at necropsy [27]. We performed histology on lung tissue on day 4 post T cell transfer (Fig.…”

Section: Increased Autoimmunity Induced By Egr-3 -/-Autoreactive T Cellsmentioning

confidence: 99%

“…C3-HA-expressing transgenic (recipient) mice have been described [27]. The hemagglutinin gene derived from influenza virus A/PR/8/34 (Mount Sinai strain), placed under the control of the rat C3 promoter, was established on the B10.D2 background homozygous for Thy1.2.…”

Section: C3-ha Tolerance Modelmentioning

confidence: 99%

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

et al. 2008

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“…6-8 Among the new targets are co-inhibitory receptors such as lymphocyte activation gene 3 (LAG-3), an immunosuppressive receptor expressed on activated T lymphocytes and T-regulatory lymphocytes, T cell immunoglobulin and mucin-3 (TIM3), T cell immunoglobulin and ITIM domain (TIGIT), which are expressed on exhausted CD8 + T cells in tumors. 9-11 Besides improving CD8 + T cell function, LAG-3, TIM3, and TIGIT blockade is expected to affect tumor tissue Treg cells and interleukin (IL)-10-producing Tr1 cells, with TIM3 and TIGIT blockade also potentially improving dendritic cell phenotype. B- and T-lymphocyte attenuator (BTLA) is another co-inhibitory receptor whose expression is induced during activation of T cells, leading to inhibition of human CD8 + cancer-specific T cells.…”

Section: Introductionmentioning

confidence: 99%

Massive parallel screening of phage libraries for the generation of repertoires of human immunomodulatory monoclonal antibodies

Sasso

D’Avino

Passariello

et al. 2018

mAbs

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Immune checkpoints are emerging as novel targets for cancer therapy, and antibodies against them have shown remarkable clinical efficacy with potential for combination treatments to achieve high therapeutic index. This work aims at providing a novel approach for the generation of several novel human immunomodulatory antibodies capable of binding their targets in their native conformation and useful for therapeutic applications.We performed a massive parallel screening of phage libraries by using for the first time activated human lymphocytes to generate large collections of single-chain variable fragments (scFvs) against 10 different immune checkpoints: LAG-3, PD-L1, PD-1, TIM3, BTLA, TIGIT, OX40, 4-1BB, CD27 and ICOS. By next-generation sequencing and bioinformatics analysis we ranked individual scFvs in each collection and identified those with the highest level of enrichment.As a proof of concept of the quality/potency of the binders identified by this approach, human IgGs from three of these collections (i.e., PD-1, PD-L1 and LAG-3) were generated and shown to have comparable or better binding affinity and biological activity than the clinically validated anti-PD-1 mAb nivolumab.The repertoires generated in this work represent a convenient source of agonistic or antagonistic antibodies against the ‘Checkpoint Immunome’ for preclinical screening and clinical implementation of optimized treatments.

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“…To date, Tregs are best characterized by FOXP3-expression, whose transcription is fundamental for both differentiation and function 8 , complemented by additional markers such as CD25, GITR, LAG3 or low CD127 expression [9][10][11] [12][13][14] . Indeed, successful treatment of allergy by allergen-specific immunotherapy may depend on induction of Tregs 6,15 .…”

Section: Introductionmentioning

confidence: 99%