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Mechanisms of CD4+ T cell heterogeneity: how do T cells decide?

English title Mechanisms of CD4+ T cell heterogeneity: how do T cells decide?
Applicant King Carolyn
Number 157520
Funding scheme SNSF Professorships
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.01.2016 - 31.12.2019
Approved amount 1'701'831.00
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Keywords (5)

regulatory T cell; TCR affinity; CD4+ T cell; infection; asymmetric division

Lay Summary (German)

Lead
Unser Immunsystem hat uns mit einem Schutz gegen eine grosse Anzahl von verschiedenen Infektionen ausgestattet. CD4+ T-Zellen haben die einzigartige Fähigkeit in verschiedene pathogen-angepasste und spezialisierte Effektor- und Gedächtniszellen zu differenzieren. Eine langandauernde Frage in der T-Zellen Biologie ist wie diese neue Tochterzellen mit derart unterschiedlichen Zellschicksalen erzeugen.
Lay summary

Unser Immunsystem hat uns mit einem Schutz gegen eine grosse Anzahl von verschiedenen Infektionen ausgestattet. CD4+ T-Zellen haben die einzigartige Fähigkeit in verschiedene pathogen-angepasste und spezialisierte Effektor- und Gedächtniszellen zu differenzieren. Eine langandauernde Frage in der T-Zellen Biologie ist wie diese neue Tochterzellen mit derart unterschiedlichen Zellschicksalen erzeugen.

Unsere ersten Daten deuten darauf hin, dass die Affinität einer T-Zelle zum zugehörigen Antigen (Ausmass der Stimulation)eine wichtige Komponente der T-Zell Differenzierung ist. Wie Unterschiede in T-Zell Stimulation auf der Ebene der Signalübertragung initiiert und auf Zellen mit verschiedenen Schicksalen übersetzt wird ist momentan noch nicht geklärt.

Unser Labor bedient sich sowohl bei Infektions- als auch Toleranzmodellen und fokussiert sich auf hauptsächlich auf zwei ausgedehnte Fragestellungen: (i) Wie reguliert die Signalstärke der T-Zelle die Qualität, das Ausmass und die Flexibilität von Immunantworten durch CD4 T-Zellen? (ii) Was sind die molekularen Mechanismen welche die Signalstärke der T-Zellen mit der Bildung von heterogenen CD4 T-Zell-Schicksalen reguliert?

 

Direct link to Lay Summary Last update: 12.02.2016

Lay Summary (English)

Lead
We hypothesize that TCR affinity will have a major impact on the induction of asymmetric division and subsequent shaping of effector CD4+ T cell responses. Using models of both infection and tolerance my lab will focus on two broad questions: (i) how does TCR signal strength regulate the quality and extent of CD4 differentiation; and (ii) what are the molecular mechanisms that link TCR signal strength with the generation of heterogeneous CD4+T cell fates?
Lay summary

Aim 1: Dissect the role of antigen affinity on TCR signaling and early T cell differentiation.  We have shown that CD4+ T cells responding during an infection can discriminate between antigen affinity and antigen dose, resulting in distinct types of effector and memory cell generation.  In this aim we will examine the effect of antigen affinity and dose on the activation, accumulation and subcellular localization of proximal and distal TCR signaling components.  Our goal is to clarify the molecular mechanisms behind segregation of TCR induced responses.

Aim 2: Investigate the contribution of of asymmetric division to CD4+ T cell differentiation.  One way that heterogeneous T cell fates can be achieved is through asymmetric cell division.  The experiments in this aim intend to elucidate if and how TCR affinity defines a threshold for asymmetric division in CD4+ T cells.

Aim 3: How do regulatory T cells (Tregs) modulate effector T cell responses during infection? Our preliminary data indicate a role for Tregs in the balanced differentiation of polyclonal CD4+ effector T cells during infection. The experiments in this aim will assess the efficacy and impact of Treg suppression on high versus low affinity activated T cells.

Direct link to Lay Summary Last update: 12.02.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
CD4+ Memory T Cells at Home in the Tissue: Mechanisms for Health and Disease
Schreiner David, King Carolyn G. (2018), CD4+ Memory T Cells at Home in the Tissue: Mechanisms for Health and Disease, in Frontiers in Immunology, 9, 1.
Affinity for self antigen selects Treg cells with distinct functional properties.
Wyss Lena, Stadinski Brian D, King Carolyn G, Schallenberg Sonja, McCarthy Nicholas I, Lee Jun Young, Kretschmer Karsten, Terracciano Luigi M, Anderson Graham, Surh Charles D, Huseby Eric S, Palmer Ed (2016), Affinity for self antigen selects Treg cells with distinct functional properties., in Nature immunology, 17(9), 1093-101.
Memory CD8(+) T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function.
Balmer Maria L, Ma Eric H, Bantug Glenn R, Grählert Jasmin, Pfister Simona, Glatter Timo, Jauch Annaïse, Dimeloe Sarah, Slack Emma, Dehio Philippe, Krzyzaniak Magdalena A, King Carolyn G, Burgener Anne-Valérie, Fischer Marco, Develioglu Leyla, Belle Réka, Recher Mike, Bonilla Weldy V, Macpherson Andrew J, Hapfelmeier Siegfried, Jones Russell G, Hess Christoph (2016), Memory CD8(+) T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function., in Immunity, 44(6), 1312-24.

Collaboration

Group / person Country
Types of collaboration
Justin Taylor, Fred Hutchinson United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Timm Schroeder, ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Michelle Linterman, Babraham Institute Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
John McKinney, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Daniel Pinschewer, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Masters in Immunology and Inflammation symposium Individual talk Survival and fitness in the CD4 memory T cell compartment 19.11.2018 Strasbourg, France King Carolyn;
Germinal center meetng Individual talk Hold your breath for TFH memory 05.10.2018 Toulouse, France King Carolyn;
Job interview Individual talk Regulation and dynamics of T cell memory 07.06.2018 Cambridge, Great Britain and Northern Ireland King Carolyn;
Keystone: Immunological Memory Poster Survival and fitness in the CD4 memory T cell compartment 25.02.2018 Austin, Texas, United States of America King Carolyn;
Department of Biomedicine Research Day Individual talk Survival and fitness in the CD4 memory T cell compartment 18.01.2018 Basel, Switzerland King Carolyn;
Seminar for Institut für Medizinische Mikrobiologie Immunologie und Hygiene, TU München Individual talk Regulation and Dynamics of T cell fate 12.06.2017 Munich, Germany Swarnalekha Nivedya;
Upper Rhine Immunology meeting Individual talk Regulation and Dynamics of T cell fate 19.05.2017 Strasbourg, France King Carolyn;
Seminar for Institute of Molecular Genetics Individual talk Regulation and Dynamics of T cell fate 19.04.2017 Prague, Czech Republic King Carolyn; Schreiner David;
University of Basel, Transplant Immunology symposium Individual talk Regulation and Dynamics of T cell fate 29.11.2016 Basel, Switzerland King Carolyn;
University of Freiburg Individual talk Regulation and Dynamics of T cell fate 07.11.2016 Freiburg, Germany King Carolyn;
University of Basel Immunology Community Poster Poster 31.10.2016 Engelberg, Switzerland King Carolyn; Swarnalekha Nivedya;
Babraham Institute Individual talk Regulation and Dynamics of T cell fate 29.09.2016 Cambridge, Great Britain and Northern Ireland King Carolyn;
University of Colorado, Denver Individual talk Regulation and Dynamics of T cell fate 07.06.2016 Denver, United States of America King Carolyn;


Awards

Title Year
Alumnipreis, Medical Faculty of the University of Basel 2016

Associated projects

Number Title Start Funding scheme
142645 The role of TCR affinity in CD4+ T cell asymmetric division and differentiation 01.01.2013 Ambizione
187200 Mechanisms of CD4+ T cell heterogeneity: how do T cells decide? 01.01.2020 SNSF Professorships

Abstract

CD4+ T cells are critical regulators of health and disease. Defects in T cell function can result in a variety of immune disorders including susceptibility to infection and the development of autoimmunity. T cell receptor (TCR) recognition of peptide:MHC (pMHC) is an essential first step in the initiation of a T cell response. Although the strength of TCR-pMHC interactions has been shown to directly modulate T cell fitness and clonal dominance within the Th compartment, how this influences effector and memory differentiation during infection is not well understood. Our preliminary data reveal distinct influences of antigen affinity and antigen dose on CD4+ T cells responding during infection. How these differences are initiated at the TCR signaling level and translated into diverse cell fates is currently unknown. Using models of both infection and tolerance my lab will focus on two broad questions: (i) how does TCR signal strength regulate the quality and extent of CD4 differentiation; and (ii) what are the molecular mechanisms that link TCR signal strength with the generation of heterogeneous CD4+T cell fates?
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