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Studies on T cell activation, differentiation and plasticity in humans

English title Studies on T cell activation, differentiation and plasticity in humans
Applicant Sallusto Federica
Number 149475
Funding scheme Project funding (Div. I-III)
Research institution Istituto di Ricerca in Biomedicina (IRB)
Institution of higher education Università della Svizzera italiana - USI
Main discipline Immunology, Immunopathology
Start/End 01.10.2013 - 30.09.2016
Approved amount 806'225.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Molecular Biology

Keywords (6)

chemokine receptors; T helper subsets; memory T cell subsets; TCR repertoire; cytokine plasticity; T lymphocytes

Lay Summary (Italian)

Lead
Questo progetto è centrato su questioni fondamentali che riguardano i linfociti T. Queste cellule del sistema immunitario, svolgono un ruolo importante nella protezione dell'ospite contro patogeni, ma possono anche causare patologie quali autoimmunità e allergie. Lo scopo del progetto è quello di investigare l'eterogeneità delle cellule T effettrici e della memoria indotte da diversi patogeni, autoantigeni o allergeni, e di definire la relazione esistente tra questi diversi tipi cellulari.
Lay summary
Il progetto si articola in due sottoprogetti principali. Nel primo si studierà la frequenza e la classe delle cellule T generate in risposta a diversi patogeni in vivo. Nel secondo sottoprogetto si studieranno a livello molecolare i meccanismi alla base della differenziazione delle cellule T e che controllano l'espressione di molecole effettrici, quali ad esempio le citochine. Ci aspettiamo che questi studi possano espandere significativamente la nostra comprensione di base della biologia delle cellule T e possano avere implicazioni traslazionali per la vaccinazione e l’immunoterapia. Il progetto farà uso di nuove tecnologie, come la citometria a flusso multiparametrica, le librerie di cellule T, e “next-generation sequencing”, al fine di analizzare la risposta immunitaria antigene-specifica a livello clonale nell’uomo.
Direct link to Lay Summary Last update: 08.11.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
T cells in patients with narcolepsy target self-antigens of hypocretin neurons
Latorre Daniela, Kallweit Ulf, Armentani Eric, Foglierini Mathilde, Mele Federico, Cassotta Antonino, Jovic Sandra, Jarrossay David, Mathis Johannes, Zellini Francesco, Becher Burkhard, Lanzavecchia Antonio, Khatami Ramin, Manconi Mauro, Tafti Mehdi, Bassetti Claudio L., Sallusto Federica (2018), T cells in patients with narcolepsy target self-antigens of hypocretin neurons, in Nature, 562(7725), 63-68.
An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells
Aschenbrenner Dominik, Foglierini Mathilde, Jarrossay David, Hu Dan, Weiner Howard L., Kuchroo Vijay K., Lanzavecchia Antonio, Notarbartolo Samuele, Sallusto Federica (2018), An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells, in Nature Immunology, 19(10), 1126-1136.
L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity
Geiger Roger, Rieckmann Jan C., Wolf Tobias, Basso Camilla, Feng Yuehan, Fuhrer Tobias, Kogadeeva Maria, Picotti Paola, Meissner Felix, Mann Matthias, Zamboni Nicola, Sallusto Federica, Lanzavecchia Antonio (2016), L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity, in Cell, 167(3), 829-842.e13.
Heterogeneity of Human CD4(+) T Cells Against Microbes.
Sallusto Federica (2016), Heterogeneity of Human CD4(+) T Cells Against Microbes., in Annual review of immunology, 34, 317-34.
Antigen-Specific Th17 Cells Are Primed by Distinct and Complementary Dendritic Cell Subsets in Oropharyngeal Candidiasis.
Trautwein-Weidner Kerstin, Gladiator André, Kirchner Florian R, Becattini Simone, Rülicke Thomas, Sallusto Federica, LeibundGut-Landmann Salomé (2015), Antigen-Specific Th17 Cells Are Primed by Distinct and Complementary Dendritic Cell Subsets in Oropharyngeal Candidiasis., in PLoS pathogens, 11(10), 1005164-1005164.
ERK phosphorylation and miR-181a expression modulate activation of human memory TH17 cells.
Mele Federico, Basso Camilla, Leoni Cristina, Aschenbrenner Dominik, Becattini Simone, Latorre Daniela, Lanzavecchia Antonio, Sallusto Federica, Monticelli Silvia (2015), ERK phosphorylation and miR-181a expression modulate activation of human memory TH17 cells., in Nature communications, 6, 6431-6431.
IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations.
Okada Satoshi, Markle Janet G, Deenick Elissa K, Mele Federico, Averbuch Dina, Lagos Macarena, Alzahrani Mohammed, Al-Muhsen Saleh, Halwani Rabih, Ma Cindy S, Wong Natalie, Soudais Claire, Henderson Lauren A, Marzouqa Hiyam, Shamma Jamal, Gonzalez Marcela, Martinez-Barricarte Rubén, Okada Chizuru, Avery Danielle T, Latorre Daniela, Deswarte Caroline, Jabot-Hanin Fabienne, Torrado Egidio, Fountain Jeffrey, Belkadi Aziz (2015), IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations., in Science (New York, N.Y.), 349(6248), 606-13.
T cell immunity. Functional heterogeneity of human memory CD4⁺ T cell clones primed by pathogens or vaccines.
Becattini Simone, Latorre Daniela, Mele Federico, Foglierini Mathilde, De Gregorio Corinne, Cassotta Antonino, Fernandez Blanca, Kelderman Sander, Schumacher Ton N, Corti Davide, Lanzavecchia Antonio, Sallusto Federica (2015), T cell immunity. Functional heterogeneity of human memory CD4⁺ T cell clones primed by pathogens or vaccines., in Science (New York, N.Y.), 347(6220), 400-6.

Collaboration

Group / person Country
Types of collaboration
Alessandro Sette, LJI, La Jolla United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Silvia Monticelli, IRB, Bellinzona Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Gioacchino Natoli, IFOM Milan Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Ton N. Schumacher, Netherlands Cancer Institute, Amsterdam Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Salomé LeibundGut, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Jean Laurent Casanova, Rockefeller University, New York United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
13th International Congress of Neuroimmunology Poster Dissecting autoreactive T cell response in CNS autoimmunity 26.09.2016 Jerusalem, Israel Armentani Eric;
4th Annual Immunogenomics Conference Talk given at a conference Human T cell repertoires in immunity, autoimmunity and allergy 26.09.2016 Huntsville, United States of America Sallusto Federica;
International Conference on Human and Translational Immunology Talk given at a conference T cell functions in autoimmunity and immunodeficiencies 16.09.2016 Rhodes, Greece Sallusto Federica;
CIML 40 Years Anniversary Talk given at a conference T cells, B cells and Antigen presenting cells in humans 14.09.2016 Marseille, France Sallusto Federica;
9th MIM PhD program student retreat Talk given at a conference T helper cell diversity in allergic responses 28.08.2016 Grindelwald, Switzerland Natali Sara;
International Congress of Immunology Talk given at a conference Isolation and characterization of hypocretin-reactive CD4+ T cells in narcoleptic patients 21.08.2016 Melbourne, Australia Latorre Daniela;
International Congress of Immunology Talk given at a conference Human Th subsets in immunity and autoimmunity 21.08.2016 Melbourne, Australia Sallusto Federica;
Seminar, La Jolla Institute for Allergy & Immunology Individual talk Memory T cells in protective and pathogenic immune responses 19.07.2016 La Jolla, United States of America Sallusto Federica;
Gordon Research Conference “Immunochemistry & Immunobiology” Talk given at a conference Functional Heterogeneity of Human Memory CD4+ T Cells 19.06.2016 Barga, Italy Sallusto Federica;
5th Swiss MedLab Congres Poster Class and specificity of T cells against C. albicans in normal and pathological conditions 14.06.2016 Bern, Switzerland De Gregorio Corinne;
Seminar, Institut Curie Talk given at a conference The human T cell response in health and disease 13.06.2016 Paris, France Sallusto Federica;
Gordon Research Conference “Chemotactic Cytokines” Talk given at a conference Human T Cell Subsets in Immunity, Autoimmunity, and Allergy 29.05.2016 Girona, Spain Sallusto Federica;
HSM-2 Immunology Symposium “Immunotolerance: Moving towards Clinical application” Talk given at a conference Functional Heterogeneity of Human CD4 T Cells 17.05.2016 Zurich, Switzerland Sallusto Federica;
Seminar, CHU Purpan Individual talk Functional T Cell Subsets in Human Health and Disease 12.05.2016 Toulouse, France Sallusto Federica;
Annual Congress Swiss Society for Allergology and Immunology Talk given at a conference Isolation and characterization of hypocretin-reactive CD4+ T cells in narcoleptic patients 28.04.2016 Montreux, Switzerland Latorre Daniela;
Clinical Immunology Society, Annual Meeting Talk given at a conference Dissecting the Heterogeneity of Human Memory T Helper Cells 14.04.2016 Boston, United States of America Sallusto Federica;
XXVIII Wolfsberg Meeting Talk given at a conference Unconventional T cell response to allergens 08.02.2016 Wolfsberg, Switzerland Natali Sara;
Nobel Symposium on Adaptive Immunity: Defense and Attack Talk given at a conference Molecular and Cellular Regulation of the Human T Cell Response 10.06.2015 Stockholm, Sweden Sallusto Federica;
American Association of Immunologists, Annual Meeting Talk given at a conference Regulation of Cytokine Genes in Human Th17 cells 08.05.2015 New Orleans, United States of America Sallusto Federica;
Seminar University of Chicago Individual talk Dissecting the human T cell response in immunity, autoimmunity and allergy 23.04.2015 Chicago, United States of America Sallusto Federica;
CSHL Meeting “Fundamental Immunology & Its Therapeutic Potential” Talk given at a conference Generation of multiple T cell fates by pathogens or vaccines 14.04.2015 Cold Spering Harbor, United States of America Sallusto Federica;
Keystone Symposium “T Cells: Regulation and Effector Function” Talk given at a conference The human T cell response to microbes 29.03.2015 Snowbird, United States of America Sallusto Federica;
Annual Congress Swiss Society for Allergology and Immunology Poster Heterogeneity of allergen-reactive human CD4 T lymphocytes 12.03.2015 Basel, Switzerland Natali Sara;
Keystone Symposium "T Cells: Regulation and Effector Function" Poster Generation of multiple fates by priming of single human naïve CD4+ T cells 04.03.2015 Snowbird, United States of America Latorre Daniela;
XXVII Wolfsberg Meeting of Swiss PhD students Talk given at a conference T cell class and specificity in health and disease 25.02.2015 Wolfsberg, Switzerland De Gregorio Corinne;
Seminar The Rockefeller University Individual talk Dissecting the human T cell response in immunity, autoimmunity and allergy 05.02.2015 New York, United States of America Sallusto Federica;
Midwinter Conference Talk given at a conference T cell subsets in immunity, autoimmunity and allergy 17.01.2015 Seefeld, Austria Sallusto Federica;
Midwinter Conference 2015 Poster Generation of multiple fates by priming of single human naïve CD4+ T cells 17.01.2015 Seefeld, Austria Latorre Daniela;
Dutch Society for Immunology, 50th Anniversary Congress Talk given at a conference Class and Specificity of the Human T Cell Response to Pathogens and Vaccines 17.12.2014 Kaatsheuvel, Netherlands Sallusto Federica;
Fondation René Touraine Talk given at a conference Human Th17 subsets 05.12.2014 Paris, France Sallusto Federica;
Seminar, University of Basel Individual talk Class and Specificity of the Human T Cell Response in Health and Disease 13.11.2014 Basel, Switzerland Sallusto Federica;
12th Congress International Society of Neuroimmunology Talk given at a conference Class and Specificity of the Human T Cell Response in Health and Disease 09.11.2014 Mainz, Germany Sallusto Federica;
XXXIX Meeting of the Brazilian Society of Immunology Talk given at a conference Class and Specificity of the Human T Cell Response to Pathogens and Vaccines 18.10.2014 Buzios, Brazil Sallusto Federica;
3rd International Conference on Immune Tolerance Talk given at a conference T cell activation, migration, and immune regulation  28.09.2014 Amsterdam, Netherlands Sallusto Federica;
Annual Meeting of the German Society for Immunology Talk given at a conference Diversity of the T Cell Responses by Pathogens or Vaccines 20.09.2014 Bonn, Germany Sallusto Federica;
International Symposium on Dendritic Cells in Fundamental and Clinical Immunology Talk given at a conference Induction of Heterogeneous T Cell Responses by Pathogens or Vaccines 14.09.2014 Tour, France Sallusto Federica;
7th MIM PhD program student retreat Poster Class and specificity of T cells against C. albicans in normal and pathological conditions 04.09.2014 Wildhaus, Switzerland De Gregorio Corinne;
Seminar, ETHZ – D-BIOL Individual talk Dissecting the heterogeneity of human memory T cells primed by pathogens 19.08.2014 Zurich, Switzerland Sallusto Federica;
Gordon Research Conference “Immunochemistry & Immunobiology” Talk given at a conference Dissecting the human T cell response to pathogens and vaccines 01.07.2014 Newry, United States of America Sallusto Federica;
FASEB Conference “Biology of the Immune System” Talk given at a conference Composition of the human naive and memory T cell repertoires 29.06.2014 Snowmass, United States of America Sallusto Federica;
Riken IMS-JSI International Symposium on Immunology Talk given at a conference Diversity and plasticity of T cell responses in humans 26.06.2014 Yokohama, Japan Sallusto Federica;
EMBO Conference on Lymphocyte Signalling Talk given at a conference Dissecting the human immunological memory for pathogens 17.05.2014 Bertinoro, Italy Sallusto Federica;
5th Australasian Vaccine & Immunotherapeutics Development Meeting Talk given at a conference Class and Specificity of the Human T Cell Response to Pathogens and Vaccines 07.05.2014 Melbourne, Australia Sallusto Federica;
22nd Annual Henry Kunkel Society Meeting Talk given at a conference Class and Specificity of the Human T Cell Response in Health and Disease 03.04.2014 New York, United States of America Sallusto Federica;
World Immune Regulation Meeting Poster IL-2 signaling controls the rapid turnover of the Foxp3 transcription factor in regulatory T cells 19.03.2014 Davos, Switzerland Goldstein Jérémie;
3rd NIF Winter School on Advanced Immunology Talk given at a conference Effector and memory T cells in human 18.01.2014 Awaji Island, Japan Sallusto Federica;
Keystone Symposium “Emerging Cytokine Network” Talk given at a conference Dissecting the human T-cell response to pathogens and vaccines 17.01.2014 Vancouver, Canada Sallusto Federica;
MIM Program – 8th Introductory Course Talk given at a conference Studies on human T cell response: differentiation, migration and function 13.01.2014 Zurich, Switzerland Sallusto Federica;
Interdisziplinäres Symposium “Inflammation and Immunology” Talk given at a conference The many faces of human Th17 cells 20.11.2013 Munich, Germany Sallusto Federica;
CSHL Meeting “Harnessing Immunity to Prevent & Treat Disease” Talk given at a conference Human memory T cell repertoires: linking clonal size, specificity and function 20.11.2013 Cold Spering Harbor, United States of America Sallusto Federica;
Bern Immunology Club Individual talk Effector, regulatory and memory T cell subsets in humans 30.10.2013 Bern, Switzerland Sallusto Federica;
EFIS-EJI Ruggero Ceppellini Advanced School of Immunology Talk given at a conference Dissecting the human T-cell response to pathogens and vaccines 16.10.2013 Castellammare di Stabia, Italy Sallusto Federica;


Associated projects

Number Title Start Funding scheme
137127 ProDoc Cell Migration Research Module I: Immune cell migration in immunosurveillance and inflammation 01.10.2011 ProDoc
170213 Studies on T cell activation, differentiation and plasticity in humans 01.10.2016 Project funding (Div. I-III)
170213 Studies on T cell activation, differentiation and plasticity in humans 01.10.2016 Project funding (Div. I-III)
131092 Effector and memory T cell subsets in man and mouse 01.07.2010 Project funding (Div. I-III)

Abstract

The effectiveness and robustness of the immune response is dependent on different types of effector and memory T cells capable of migrating to different tissues and of producing a variety of cytokines in response to diverse types of pathogens. In principle this response could be built on: i) multiple clones, each performing a given function; ii) multiple functions performed by distinct descendants of a single clone; or, iii) any combination of the two. For this reason, understanding the distribution of antigen-specific T cell clones within effector and memory subsets is of both fundamental and practical importance. This proposal is centered on fundamental questions that pertain to T lymphocyte functions in protection and pathology. We aim at defining the lineage relationship between different memory T cell subsets and between T helper cells with polarized or mixed cytokine profiles, and the natural and therapeutic plasticity of effector and memory T cells at different stages of differentiation. The proposal builds on our knowledge of human T cell differentiation and on the identification of different types of effector and memory T cell subsets, as well as on our early studies on the epigenetic control of human CD4 T cell polarization and plasticity. We will take advantage of multiparametric flow cytometry and cell sorting, high throughput T cell cloning, and next generation sequencing to analyse the human antigen-specific immune response at the clonal level. The project is organized in two main subprojects. The first will address the distribution of memory and effector T cells within individual expanded clones of antigen-specific T cells primed in vivo by different classes of antigens. We will establish, at the clonal level, the lineage relationship of effector and memory T cell subsets, such as T cells producing IFN-?, IL-4, IL-17 and IL-22, alone or in different combinations, or circulating follicular helper T cells and central memory and effector memory T cells. The second subproject will address at the molecular level the mechanisms of T cell differentiation and plasticity that control expression of effector cytokines. The hypotheses tested are strongly supported by preliminary observations from our own laboratory as well as from the biomedical literature. We expect that these studies will significantly expand our basic understanding of T cell biology and will have translational implications for vaccination and immunotherapy.
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