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Article ; Online: Mind the GAP: RASA2 and RASA3 GTPase-activating proteins as gatekeepers of T cell activation and adhesion.

Johansen, Kristoffer H / Golec, Dominic P / Okkenhaug, Klaus / Schwartzberg, Pamela L

2023 Volume 44, Issue 11, Page(s) 917–931

Abstract: Following stimulation, the T cell receptor (TCR) and its coreceptors integrate multiple intracellular signals to initiate T cell proliferation, migration, gene expression, and metabolism. Among these signaling molecules are the small GTPases RAS and RAP1, ...

Abstract	Following stimulation, the T cell receptor (TCR) and its coreceptors integrate multiple intracellular signals to initiate T cell proliferation, migration, gene expression, and metabolism. Among these signaling molecules are the small GTPases RAS and RAP1, which induce MAPK pathways and cellular adhesion to activate downstream effector functions. Although many studies have helped to elucidate the signaling intermediates that mediate T cell activation, the molecules and pathways that keep naive T cells in check are less understood. Several recent studies provide evidence that RASA2 and RASA3, which are GAP1-family GTPase-activating proteins (GAPs) that inactivate RAS and RAP1, respectively, are crucial molecules that limit T cell activation and adhesion. In this review we describe recent data on the roles of RASA2 and RASA3 as gatekeepers of T cell activation and migration.
MeSH term(s)	Humans ; GTPase-Activating Proteins/genetics ; GTPase-Activating Proteins/metabolism ; Signal Transduction/physiology ; Cell Adhesion/physiology ; T-Lymphocytes/metabolism ; ras GTPase-Activating Proteins
Chemical Substances	GTPase-Activating Proteins ; RASA2 protein, human ; ras GTPase-Activating Proteins
Language	English
Publishing date	2023-10-18
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2023.09.002
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Article ; Online: PI3K in T Cell Adhesion and Trafficking.

Johansen, Kristoffer H / Golec, Dominic P / Thomsen, Julie H / Schwartzberg, Pamela L / Okkenhaug, Klaus

Frontiers in immunology

2021 Volume 12, Page(s) 708908

Abstract: PI3K signalling is required for activation, differentiation, and trafficking of T cells. PI3Kδ, the dominant PI3K isoform in T cells, has been extensively characterised using PI3Kδ mutant mouse models and PI3K inhibitors. Furthermore, characterisation of ...

Abstract	PI3K signalling is required for activation, differentiation, and trafficking of T cells. PI3Kδ, the dominant PI3K isoform in T cells, has been extensively characterised using PI3Kδ mutant mouse models and PI3K inhibitors. Furthermore, characterisation of patients with Activated PI3K Delta Syndrome (APDS) and mouse models with hyperactive PI3Kδ have shed light on how increased PI3Kδ activity affects T cell functions. An important function of PI3Kδ is that it acts downstream of TCR stimulation to activate the major T cell integrin, LFA-1, which controls transendothelial migration of T cells as well as their interaction with antigen-presenting cells. PI3Kδ also suppresses the cell surface expression of CD62L and CCR7 which controls the migration of T cells across high endothelial venules in the lymph nodes and S1PR1 which controls lymph node egress. Therefore, PI3Kδ can control both entry and exit of T cells from lymph nodes as well as the recruitment to and retention of T cells within inflamed tissues. This review will focus on the regulation of adhesion receptors by PI3Kδ and how this contributes to T cell trafficking and localisation. These findings are relevant for our understanding of how PI3Kδ inhibitors may affect T cell redistribution and function.
MeSH term(s)	Animals ; Cell Adhesion ; Cell Movement ; Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Class I Phosphatidylinositol 3-Kinases/physiology ; Guanine Nucleotide Exchange Factors/physiology ; Humans ; Immunological Synapses/physiology ; Integrins/physiology ; Lymphocyte Function-Associated Antigen-1/physiology ; Mice ; Primary Immunodeficiency Diseases/etiology ; Signal Transduction/physiology ; T-Lymphocytes/physiology ; rho-Associated Kinases/physiology
Chemical Substances	Guanine Nucleotide Exchange Factors ; Integrins ; Lymphocyte Function-Associated Antigen-1 ; cytohesin-1 ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PIK3CD protein, human (EC 2.7.1.137) ; rho-Associated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2021-08-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.708908
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Article ; Online: Eosinophil trafficking in allergen-mediated pulmonary inflammation relies on IL-13-driven CCL-11 and CCL-24 production by tissue fibroblasts and myeloid cells.

Gazzinelli-Guimaraes, Pedro H / Golec, Dominic P / Karmele, Erik P / Sciurba, Joshua / Bara-Garcia, Pablo / Hill, Tom / Kang, Byunghyun / Bennuru, Sasisekhar / Schwartzberg, Pamela L / Nutman, Thomas B

The journal of allergy and clinical immunology. Global

2023 Volume 2, Issue 4, Page(s) 100131

Abstract: Background: The immunologic mechanisms underlying pulmonary type 2 inflammation, including the dynamics of eosinophil recruitment to the lungs, still need to be elucidated.: Objective: We sought to investigate how IL-13-producing T: Methods: ... ...

Abstract	Background: The immunologic mechanisms underlying pulmonary type 2 inflammation, including the dynamics of eosinophil recruitment to the lungs, still need to be elucidated. Objective: We sought to investigate how IL-13-producing T Methods: Multiparameter and molecular profiling of murine lungs with HDM-induced allergy was investigated in the absence of IL-13 signaling by using IL-13Rα1-deficient mice and separately through adoptive transfer of CD4 Results: We demonstrated through single-cell techniques that HDM-driven pulmonary inflammation displays a profile characterized by T Conclusion: Our data suggest that IL-5-dependent allergen-specific T
Language	English
Publishing date	2023-06-26
Publishing country	United States
Document type	Journal Article
ISSN	2772-8293
ISSN (online)	2772-8293
DOI	10.1016/j.jacig.2023.100131
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Article ; Online: γδ Thymocyte Maturation and Emigration in Adult Mice.

Joannou, Kevin / Golec, Dominic P / Wang, Haiguang / Henao-Caviedes, Laura M / May, Julia F / Kelly, Rees G / Chan, Rigel / Jameson, Stephen C / Baldwin, Troy A

Journal of immunology (Baltimore, Md. : 1950)

2022 Volume 208, Issue 9, Page(s) 2131–2140

Abstract: Several unique waves of γδ T cells are generated solely in the fetal/neonatal thymus, whereas additional γδ T cell subsets are generated in adults. One intriguing feature of γδ T cell development is the coordination of differentiation and acquisition of ... ...

Abstract	Several unique waves of γδ T cells are generated solely in the fetal/neonatal thymus, whereas additional γδ T cell subsets are generated in adults. One intriguing feature of γδ T cell development is the coordination of differentiation and acquisition of effector function within the fetal thymus; however, it is less clear whether this paradigm holds true in adult animals. In this study, we investigated the relationship between maturation and thymic export of adult-derived γδ thymocytes in mice. In the Rag2pGFP model, immature (CD24
MeSH term(s)	Animals ; Emigration and Immigration ; Lymphocyte Activation ; Mice ; Receptors, Antigen, T-Cell, gamma-delta ; T-Lymphocyte Subsets ; Thymocytes
Chemical Substances	Receptors, Antigen, T-Cell, gamma-delta
Language	English
Publishing date	2022-04-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2100360
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Article ; Online: RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors.

Golec, Dominic P / Henao Caviedes, Laura M / Baldwin, Troy A

Journal of immunology (Baltimore, Md. : 1950)

2016 Volume 197, Issue 5, Page(s) 1743–1753

Abstract: T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways ... ...

Abstract	T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways including the Notch and Wnt pathways. To date, Ras signaling has not been implicated in the very earliest stages of T cell differentiation, but members of a family of Ras activators called RasGRPs have been shown to be involved at multiple stages of T cell development. We examined early T cell development in mice lacking RasGRP1, RasGRP3, and RasGRPs 1 and 3. We report that RasGRP1- and RasGRP3-deficient thymi show significantly reduced numbers of early thymic progenitors (ETPs) relative to wild type thymi. Furthermore, RasGRP1/3 double-deficient thymi show significant reductions in ETP numbers compared with either RasGRP1 or RasGRP3 single-deficient thymi, suggesting that both RasGRP1 and RasGRP3 regulate the generation of ETPs. In addition, competitive bone marrow chimera experiments reveal that RasGRP1/3 double-deficient progenitors intrinsically generate ETPs less efficiently than wild type progenitors. Finally, RasGRP1/3-deficient progenitors show impaired migration toward the CCR9 ligand, CCL25, suggesting that RasGRP1 and RasGRP3 may regulate progenitor entry into the thymus through a CCR9-dependent mechanism. These data demonstrate that, in addition to Notch and Wnt, the highly conserved Ras pathway is critical for the earliest stages of T cell development and further highlight the importance of Ras signaling during thymocyte maturation.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/physiology ; Cell Differentiation ; Cell Proliferation ; Chemokines, CC/immunology ; Gene Expression Regulation ; Guanine Nucleotide Exchange Factors/deficiency ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism ; Lymphocyte Activation ; Lymphoid Progenitor Cells/immunology ; Lymphoid Progenitor Cells/physiology ; Mice ; Precursor Cells, B-Lymphoid/immunology ; Precursor Cells, B-Lymphoid/physiology ; Receptors, CCR/immunology ; Signal Transduction ; T-Lymphocytes/immunology ; T-Lymphocytes/physiology ; Thymocytes/immunology ; Thymocytes/physiology ; Thymus Gland/cytology ; Thymus Gland/immunology ; Thymus Gland/physiology ; ras Guanine Nucleotide Exchange Factors/deficiency ; ras Guanine Nucleotide Exchange Factors/genetics ; ras Guanine Nucleotide Exchange Factors/metabolism
Chemical Substances	CC chemokine receptor 9 ; Ccl25 protein, mouse ; Chemokines, CC ; Guanine Nucleotide Exchange Factors ; RasGRP3 protein, mouse ; Rasgrp1 protein, mouse ; Rasgrp2 protein, mouse ; Receptors, CCR ; ras Guanine Nucleotide Exchange Factors
Language	English
Publishing date	2016-09-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1502107
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Article ; Online: A CRISPR screen targeting PI3K effectors identifies RASA3 as a negative regulator of LFA-1-mediated adhesion in T cells.

Johansen, Kristoffer H / Golec, Dominic P / Huang, Bonnie / Park, Chung / Thomsen, Julie H / Preite, Silvia / Cannons, Jennifer L / Garçon, Fabien / Schrom, Edward C / Courrèges, Christina J F / Veres, Tibor Z / Harrison, James / Nus, Meritxell / Phelan, James D / Bergmeier, Wolfgang / Kehrl, John H / Okkenhaug, Klaus / Schwartzberg, Pamela L

Science signaling

2022 Volume 15, Issue 743, Page(s) eabl9169

Abstract: The integrin lymphocyte function-associated antigen 1 (LFA-1) helps to coordinate the migration, adhesion, and activation of T cells through interactions with intercellular adhesion molecule 1 (ICAM-1) and ICAM-2. LFA-1 is activated during the engagement ...

Abstract	The integrin lymphocyte function-associated antigen 1 (LFA-1) helps to coordinate the migration, adhesion, and activation of T cells through interactions with intercellular adhesion molecule 1 (ICAM-1) and ICAM-2. LFA-1 is activated during the engagement of chemokine receptors and the T cell receptor (TCR) through inside-out signaling, a process that is partially mediated by phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol 3,4,5-trisphosphate (PIP
MeSH term(s)	Animals ; Antigens, CD ; Cell Adhesion/genetics ; Cell Adhesion Molecules ; Clustered Regularly Interspaced Short Palindromic Repeats ; GTPase-Activating Proteins ; Intercellular Adhesion Molecule-1/metabolism ; Lymphocyte Function-Associated Antigen-1/genetics ; Lymphocyte Function-Associated Antigen-1/metabolism ; Mice ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; T-Lymphocytes/metabolism
Chemical Substances	Antigens, CD ; Cell Adhesion Molecules ; GTPase-Activating Proteins ; ICAM-2 protein, mouse ; Lymphocyte Function-Associated Antigen-1 ; RASA3 protein, mouse ; Intercellular Adhesion Molecule-1 (126547-89-5) ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137)
Language	English
Publishing date	2022-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.abl9169
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Article ; Online: Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes.

Campbell, Scott A / Golec, Dominic P / Hubert, Matt / Johnson, Janyne / Salamon, Nicole / Barr, Amy / MacDonald, Patrick E / Philippaert, Koenraad / Light, Peter E

Molecular metabolism

2020 Volume 39, Page(s) 101014

Abstract: Objectives: Our study shows that glucagon-like peptide-1 (GLP-1) is secreted within human islets and may play an unexpectedly important paracrine role in islet physiology and pathophysiology. It is known that α cells within rodent and human pancreatic ... ...

Abstract	Objectives: Our study shows that glucagon-like peptide-1 (GLP-1) is secreted within human islets and may play an unexpectedly important paracrine role in islet physiology and pathophysiology. It is known that α cells within rodent and human pancreatic islets are capable of secreting GLP-1, but little is known about the functional role that islet-derived GLP-1 plays in human islets. Methods: We used flow cytometry, immunohistochemistry, perifusions, and calcium imaging techniques to analyse GLP-1 expression and function in islets isolated from cadaveric human donors with or without type 2 diabetes. We also used immunohistochemistry to analyse GLP-1 expression within islets from pancreatic biopsies obtained from living donors. Results: We have demonstrated that human islets secrete ∼50-fold more GLP-1 than murine islets and that ∼40% of the total human α cells contain GLP-1. Our results also confirm that dipeptidyl peptidase-4 (DPP4) is expressed in α cells. Sitagliptin increased GLP-1 secretion from cultured human islets but did not enhance glucose-stimulated insulin secretion (GSIS) in islets from non-diabetic (ND) or type 2 diabetic (T2D) donors, suggesting that β cell GLP-1 receptors (GLP-1R) may already be maximally activated. Therefore, we tested the effects of exendin-9, a GLP-1R antagonist. Exendin-9 was shown to reduce GSIS by 39% and 61% in ND islets and T2D islets, respectively. We also observed significantly more GLP-1+ α cells in T2D islets compared with ND islets obtained from cadaveric donors. Furthermore, GLP-1+ α cells were also identified in pancreatic islet sections obtained from living donors undergoing surgery. Conclusions: In summary, we demonstrated that human islets secrete robust amounts of GLP-1 from an α cell subpopulation and that GLP-1R signalling may support GSIS to a greater extent in T2D islets.
MeSH term(s)	Animals ; Biomarkers ; Diabetes Mellitus, Type 2/etiology ; Diabetes Mellitus, Type 2/metabolism ; Gene Expression ; Glucagon/metabolism ; Glucagon-Like Peptide 1/biosynthesis ; Glucagon-Like Peptide 1/genetics ; Glucagon-Secreting Cells/metabolism ; Glucose/metabolism ; Humans ; Immunophenotyping ; Insulin/metabolism ; Insulin-Secreting Cells/metabolism ; Islets of Langerhans/cytology ; Islets of Langerhans/metabolism ; Mice
Chemical Substances	Biomarkers ; Insulin ; Glucagon-Like Peptide 1 (89750-14-1) ; Glucagon (9007-92-5) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2020-05-12
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2020.101014
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Article ; Online: Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells.

Santer, Deanna M / Minty, Gillian E S / Golec, Dominic P / Lu, Julia / May, Julia / Namdar, Afshin / Shah, Juhi / Elahi, Shokrollah / Proud, David / Joyce, Michael / Tyrrell, D Lorne / Houghton, Michael

PLoS pathogens

2020 Volume 16, Issue 4, Page(s) e1008515

Abstract: Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to ... ...

Abstract	Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-λR1 expression and measure the downstream effects of IFN-λ3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8+ T cells, but not monocytes, neutrophils, natural killer cells, and CD4+ T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by higher expression of the soluble variant of IFN-λR1 (sIFN-λR1), which significantly reduced ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells or liver epithelial cells. T-cell receptor stimulation potently, and specifically, upregulated membrane-bound IFNLR1 expression in CD4+ T cells, leading to greater antiviral gene induction, and inhibition of human immunodeficiency virus type 1 infection. Collectively, our data demonstrate IFN-λ3 directly interacts with the human adaptive immune system, unlike what has been previously shown in published mouse models, and that type III IFNs could be potentially utilized to suppress both mucosal and blood-borne viral infections.
MeSH term(s)	Animals ; B-Lymphocytes/drug effects ; B-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/immunology ; Cell Line ; Epithelial Cells/metabolism ; Gene Expression ; HIV Infections/immunology ; HIV Infections/pathology ; HIV Infections/virology ; HIV-1/immunology ; Humans ; Interferon alpha-2/pharmacology ; Interferons/immunology ; Interferons/pharmacology ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/metabolism ; Liver/metabolism ; Liver/pathology ; Lung/metabolism ; Lung/pathology ; Mice ; RNA Splicing ; Receptors, Interferon/biosynthesis ; Receptors, Interferon/genetics ; Receptors, Interferon/immunology ; Virus Diseases/genetics ; Virus Diseases/immunology ; Virus Diseases/metabolism ; Interferon Lambda
Chemical Substances	interferon-lambda, human ; IFNLR1 protein, human ; IFNLR1 protein, mouse ; Interferon alpha-2 ; Receptors, Interferon ; Interferons (9008-11-1) ; Interferon Lambda
Keywords	covid19
Language	English
Publishing date	2020-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1008515
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Article ; Online: RasGRP1, but not RasGRP3, is required for efficient thymic β-selection and ERK activation downstream of CXCR4.

Golec, Dominic P / Dower, Nancy A / Stone, James C / Baldwin, Troy A

PloS one

2013 Volume 8, Issue 1, Page(s) e53300

Abstract: T cell development is a highly dynamic process that is driven by interactions between developing thymocytes and the thymic microenvironment. Upon entering the thymus, the earliest thymic progenitors, called CD4(-)CD8(-) 'double negative' (DN) thymocytes, ...

Abstract	T cell development is a highly dynamic process that is driven by interactions between developing thymocytes and the thymic microenvironment. Upon entering the thymus, the earliest thymic progenitors, called CD4(-)CD8(-) 'double negative' (DN) thymocytes, pass through a checkpoint termed "β-selection" before maturing into CD4(+)CD8(+) 'double positive' (DP) thymocytes. β-selection is an important developmental checkpoint during thymopoiesis where developing DN thymocytes that successfully express the pre-T cell receptor (TCR) undergo extensive proliferation and differentiation towards the DP stage. Signals transduced through the pre-TCR, chemokine receptor CXCR4 and Notch are thought to drive β-selection. Additionally, it has long been known that ERK is activated during β-selection; however the pathways regulating ERK activation remain unknown. Here, we performed a detailed analysis of the β-selection events in mice lacking RasGRP1, RasGRP3 and RasGRP1 and 3. We report that RasGRP1 KO and RasGRP1/3 DKO deficient thymi show a partial developmental block at the early DN3 stage of development. Furthermore, DN3 thymocytes from RasGRP1 and RasGRP1/3 double knock-out thymi show significantly reduced proliferation, despite expression of the TCRβ chain. As a result of impaired β-selection, the pool of TCRβ(+) DN4 is significantly diminished, resulting in inefficient DN to DP development. Also, we report that RasGRP1 is required for ERK activation downstream of CXCR4 signaling, which we hypothesize represents a potential mechanism of RasGRP1 regulation of β-selection. Our results demonstrate that RasGRP1 is an important regulator of proliferation and differentiation at the β-selection checkpoint and functions downstream of CXCR4 to activate the Ras/MAPK pathway.
MeSH term(s)	Animals ; Cell Line ; Cell Proliferation ; Female ; Gene Knockout Techniques ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/immunology ; MAP Kinase Signaling System ; Male ; Mice ; Mice, Inbred C57BL ; Receptors, CXCR4/immunology ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Thymus Gland/cytology ; Thymus Gland/immunology ; Thymus Gland/metabolism ; ras Guanine Nucleotide Exchange Factors/genetics ; ras Guanine Nucleotide Exchange Factors/immunology
Chemical Substances	Guanine Nucleotide Exchange Factors ; RasGRP3 protein, mouse ; Rasgrp1 protein, mouse ; Receptors, CXCR4 ; ras Guanine Nucleotide Exchange Factors
Language	English
Publishing date	2013-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0053300
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Article ; Online: Thymic progenitors of TCRαβ

Golec, Dominic P / Hoeppli, Romy E / Henao Caviedes, Laura M / McCann, Jillian / Levings, Megan K / Baldwin, Troy A

The Journal of experimental medicine

2017 Volume 214, Issue 8, Page(s) 2421–2435

Abstract: Strong T cell receptor (TCR) signaling largely induces cell death during thymocyte development, whereas weak TCR signals induce positive selection. However, some T cell lineages require strong TCR signals for differentiation through a process termed ... ...

Abstract	Strong T cell receptor (TCR) signaling largely induces cell death during thymocyte development, whereas weak TCR signals induce positive selection. However, some T cell lineages require strong TCR signals for differentiation through a process termed agonist selection. The signaling relationships that underlie these three fates are unknown. RasGRP1 is a Ras activator required to transmit weak TCR signals leading to positive selection. Here, we report that, despite being dispensable for thymocyte clonal deletion, RasGRP1 is critical for agonist selection of TCRαβ
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/physiology ; Cell Lineage/physiology ; Female ; Guanine Nucleotide Exchange Factors/physiology ; Humans ; Intestinal Mucosa/cytology ; Intestinal Mucosa/physiology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Receptors, Antigen, T-Cell, alpha-beta/physiology ; Signal Transduction/physiology ; Stem Cells/physiology ; Thymus Gland/cytology
Chemical Substances	Guanine Nucleotide Exchange Factors ; Rasgrp1 protein, mouse ; Receptors, Antigen, T-Cell, alpha-beta
Language	English
Publishing date	2017-08-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20170844
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