气候变化领域集成服务门户(CCPortal): Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK

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DOI	10.1073/pnas.2025825118
	Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK
	Gallagher M.P.; Conley J.M.; Vangala P.; Garber M.; Reboldi A.; Berg L.J.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:35
英文摘要	The strength of peptide:MHC interactions with the T cell receptor (TCR) is correlated with the time to first cell division, the relative scale of the effector cell response, and the graded expression of activation-associated proteins like IRF4. To regulate T cell activation programming, the TCR and the TCR proximal interleukin-2-inducible T cell kinase (ITK) simultaneously trigger many biochemically separate signaling cascades. T cells lacking ITK exhibit selective impairments in effector T cell responses after activation, but under the strongest signaling conditions, ITK activity is dispensable. To gain insight into whether TCR signal strength and ITK activity tune observed graded gene expression through the unequal activation of distinct signaling pathways, we examined Erk1/2 phosphorylation or nuclear factor of activated T cells (NFAT) and nuclear factor (NF)- κB translocation in naïve OT-I CD8+ cell nuclei. We observed the consistent digital activation of NFAT1 and Erk1/2, but NF-κB displayed dynamic, graded activation in response to variation in TCR signal strength, tunable by treatment with an ITK inhibitor. Inhibitor-treated cells showed the dampened induction of AP-1 factors Fos and Fosb, NF-κB response gene transcripts, and survival factor Il2 transcripts. ATAC sequencing analysis also revealed that genomic regions most sensitive to ITK inhibition were enriched for NF-κB and AP-1 motifs. Specific inhibition of NF-κB during peptide stimulation tuned the expression of early gene products like c-Fos. Together, these data indicate a key role for ITK in orchestrating the optimal activation of separate TCR downstream pathways, specifically aiding NF-κB activation. More broadly, we revealed a mechanism by which variations in TCR signal strength can produce patterns of graded gene expression in activated T cells. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	ITK; NF-κB; NFAT; T cell activation; T cell receptor signaling
语种	英语
scopus关键词	CD8 antigen; immunoglobulin enhancer binding protein; interleukin 2; ITK protein; mitogen activated protein kinase 1; mitogen activated protein kinase 3; protein c fos; protein fos; protein kinase; T lymphocyte receptor; transcription factor AP 1; transcription factor FosB; transcription factor NFAT; unclassified drug; DNA; emt protein-tyrosine kinase; immunoglobulin enhancer binding protein; lymphocyte antigen receptor; Nfatc2 protein, mouse; protein tyrosine kinase; Tec protein-tyrosine kinase; transcription factor NFAT; animal cell; Article; cellular distribution; controlled study; enzyme inhibition; enzyme phosphorylation; Fos gene; Fosb gene; gene expression; genetic transcription; Il2 gene; mouse; nonhuman; protein motif; sequence analysis; T lymphocyte; TCR signaling; animal; cell culture; enzymology; female; gene expression regulation; genetics; immunology; lymphocyte activation; male; MAPK signaling; metabolism; signal transduction; Animals; Cells, Cultured; DNA; Female; Gene Expression Regulation; Lymphocyte Activation; Male; MAP Kinase Signaling System; Mice; NF-kappa B; NFATC Transcription Factors; Protein-Tyrosine Kinases; Receptors, Antigen, T-Cell; Signal Transduction; T-Lymphocytes
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251030
作者单位	Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, United States; Department of Immunology and Microbiology, University of Colorado, Anschutz School of Medicine, Aurora, CO 80045, United States; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, United States
推荐引用方式 GB/T 7714	Gallagher M.P.,Conley J.M.,Vangala P.,et al. Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK[J],2021,118(35).
APA	Gallagher M.P.,Conley J.M.,Vangala P.,Garber M.,Reboldi A.,&Berg L.J..(2021).Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK.Proceedings of the National Academy of Sciences of the United States of America,118(35).
MLA	Gallagher M.P.,et al."Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK".Proceedings of the National Academy of Sciences of the United States of America 118.35(2021).