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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 170213
Funding scheme Project funding (Div. I-III)
Research institution Istituto di ricerca in biomedicina (IRB) Facoltà di scienze biomedice
Institution of higher education Università della Svizzera italiana - USI
Main discipline Immunology, Immunopathology
Start/End 01.10.2016 - 30.09.2019
Approved amount 807'775.00
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Keywords (6)

chemokine receptors; T helper substes; Malaria; cytokine plasticity; T lymphocyte differentiation; TCR repertoire

Lay Summary (Italian)

Lead
Questo progetto si propone di aumentare le nostre conoscenze sulla specificità e funzione dei linfociti T. Queste cellule del sistema immunitario adattativo svolgono un ruolo importante nella protezione dell'ospite contro patogeni, come ad esempio il Plasmodium falciparum che causa la malaria, ma possono anche provocare patologie, quali l’autoimmunità e le allergie.
Lay summary
Il progetto si articola in tre sottoprogetti principali. Nel primo sottoprogetto studieremo i meccanismi per cui un singolo linfocita T naive può dare origine a un clone di cellule effettrici con diverse funzioni. Questi studi si propongono di definire i meccanismi cellulari e molecolari alla base del processo di differenziazione dei linfociti T. Nel secondo sottoprogetto, caratterizzeremo linfociti T auto-regolatori e pro-infiammatori, definiti in base alla capacità di produrre la citochina IL-10. Questi due tipi di linfociti T potrebbero giocare ruoli diversi nelle risposte immunitarie protettive o patologiche. Nel terzo sottoprogetto, che verrà svolto in collaborazione con l’Istituto tropicale e di salute pubblica svizzero (Swiss TPH), studieremo il fenotipo e la funzione dei linfociti T specifici per antigeni del Plasmodio della malaria in volontari vaccinati con sporozoiti di Plasmodium falciparum attenuati (PfSPZ Vaccine). L'obiettivo è quello di identificare marcatori che correlino con protezione o rischio di malattia ed ottenere informazioni utili per la messa a punto di vaccini più efficaci.
Direct link to Lay Summary Last update: 24.09.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
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.
Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency
Kong Xiao-Fei, Martinez-Barricarte Ruben, Kennedy James, Mele Federico, Lazarov Tomi, Deenick Elissa K., Ma Cindy S., Breton Gaëlle, Lucero Kimberly B., Langlais David, Bousfiha Aziz, Aytekin Caner, Markle Janet, Trouillet Céline, Jabot-Hanin Fabienne, Arlehamn Cecilia S. Lindestam, Rao Geetha, Picard Capucine, Lasseau Théo, Latorre Daniela, Hambleton Sophie, Deswarte Caroline, Itan Yuval, Abarca Katia, et al. (2018), Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency, in Nature Immunology, 19(9), 973-985.
Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis
Hu Dan, Notarbartolo Samuele, Croonenborghs Tom, Patel Bonny, Cialic Ron, Yang Tun-Hsiang, Aschenbrenner Dominik, Andersson Karin M., Gattorno Marco, Pham Minh, Kivisakk Pia, Pierre Isabelle V., Lee Youjin, Kiani Karun, Bokarewa Maria, Tjon Emily, Pochet Nathalie, Sallusto Federica, Kuchroo Vijay K., Weiner Howard L. (2017), Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis, in Nature Communications, 8(1), 1600-1600.

Datasets

Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis

Author Hu, Dan; Notarbartolo, Samuele; Croonenborghs, Tom; Patel, Bonny; Cialic, Ron; Yang, Tun-Hsiang; Aschenbrenner, Dominik; Andersson, Karin M.; Gattorno, Marco; Pham, Minh; Kivisakk, Pia; Pierre, Isabelle V.; Lee, Youjin; Kiani, Karun; Bokarewa, Maria; Tjon, Emily; Pochet, Nathalie; Sallusto, Federica; Kuchroo, Vijay K.; Weiner, Howard L.
Publication date 17.12.2017
Persistent Identifier (PID) GSE104024
Repository Gene Expression Omnibus (GEO)


Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency

Author Kong, Xiao-Fei; Martinez-Barricarte, Ruben; Kennedy, James; Mele, Federico; Lazarov, Tomi; Deenick, Elissa K.; Ma, Cindy S.; Breton, Gaëlle; Lucero, Kimberly B.; Langlais, David; Bousfiha, Aziz; Aytekin, Caner; Markle, Janet; Trouillet, Céline; Jabot-Hanin, Fabienne; Arlehamn, Cecilia S. Lindestam; Rao, Geetha; Picard, Capucine; Lasseau, Théo; Latorre, Daniela; Hambleton, Sophie; Deswarte, Caroline; Itan, Yuval; Abarca, Katia; et al.,
Publication date 20.09.2018
Persistent Identifier (PID) DOI
Repository Sequence Read Archive SRA


An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells

Author Aschenbrenner, Dominik; Foglierini, Mathilde; Jarrossay, David; Hu, Dan; Weiner, Howard L.; Kuchroo, Vijay K.; Lanzavecchia, Antonio; Notarbartolo, Samuele; Sallusto, Federica
Publication date 10.10.2018
Persistent Identifier (PID) DOI
Repository DOI


Collaboration

Group / person Country
Types of collaboration
Vijay K. Kuchroo / Harvard Medical School United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Jean-Laurent Casanova / The Rockefeller University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Anne Puel / Institute Imagine, Inserm France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Alessandro Sette / LIAI United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Howard L. Weiner / Harvard Medical School 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
Riken IMS-JSI International Symposium on Immunology Talk given at a conference Human T cell repertoires in health and disease 25.06.2019 Tokyo, Japan Sallusto Federica;
Pears Lecture, IIT Immunology Symposium Talk given at a conference Human T cell repertoires in health and disease 18.06.2019 London, Great Britain and Northern Ireland Sallusto Federica;
Gordon Research Conference “Immunochemistry and Immunobiology” Talk given at a conference Keynote Session: Initiation and Modulation of the Immune Response 10.06.2018 Mount Snow, United States of America Sallusto Federica;
Annual Congress American Association of Immunologists Talk given at a conference Lymphocyte diversity: matching specificity and function 06.05.2018 Austin, United States of America Sallusto Federica;
Gershon Lecture Individual talk Lymphocyte diversity: matching specificity and function 12.04.2018 New Haven, United States of America Sallusto Federica;
Keystone Symposium “Immunological Memory” Talk given at a conference Human Memory T Cell Subsets: from Phenotype to Function 01.03.2018 Austin, United States of America Sallusto Federica;
Annual Congress Australasian Society for Immunology Talk given at a conference Dissecting the heterogeneity of the human T cell response 28.11.2017 Brisbane, Australia Sallusto Federica;
Annual Congress of Swiss Society for Allergology and Immunology Talk given at a conference Heterogeneity of human CD4+ T Cells 01.06.2017 St. Gallen, Switzerland Sallusto Federica;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells IRB web site Italian-speaking Switzerland 2018

Awards

Title Year
I numeri uno 2019

Associated projects

Number Title Start Funding scheme
149475 Studies on T cell activation, differentiation and plasticity in humans 01.10.2013 Project funding (Div. I-III)
189331 New approaches to study T cell activation, differentiation and plasticity in humans 01.01.2020 Project funding (Div. I-III)
149475 Studies on T cell activation, differentiation and plasticity in humans 01.10.2013 Project funding (Div. I-III)
154483 Unraveling the immune etiology of multiple sclerosis - UnmetMS 01.10.2014 Sinergia
173586 Analysis of mycobacteria-induced T cell response in patients with inborn errors of IL-12 and IL-23 signaling 01.02.2017 International short research visits

Abstract

The current proposal is the continuation of our previous studies of the human T cell response to microbes that have advanced our understanding of CD4+ T cell functional heterogeneity, in particular with the discovery of a distinct non-classic Th1* subset involved in the response to Mycobacteria (Acosta-Rodriguez et al, 2007; Lindestam Arlehamn et al, 2013) and the characterization of two types of Th17 cells specific for extracellular bacteria or fungi (Zielinski et al, 2012). The new approaches that we have developed combining antigenic stimulation and T cell receptor (TCR) deep sequencing have also revealed that the CD4+ T cell response induced by pathogens or vaccines comprise not only clones polarized toward a single fate, but also clones whose progeny have acquired multiple fates (Becattini et al, 2015), demonstrating an unexpected degree of intraclonal diversification and suggesting a progressive and selective model of CD4+ T cell differentiation (Sallusto, 2016). In Aim 1 of the current proposal, we will address the mechanisms whereby a single naïve T cell can give rise to daughter cells with identical TCR but that adopt different fates. In this “one cell, multiple fates model”, the challenge is to determine whether the process is deterministic or stochastic and the temporal events leading to the heterogeneous progeny (Reiner et al, 2007). These studies should lead to a better definition on the mechanisms of T cell differentiation and on the lineage relationship between different T cell subsets and between T helper cells with polarized or mixed cytokine profiles. In Aim 2 we will further dissect the heterogeneity of human CD4+ T cell subsets, with particular emphasis on the characterization of T cells that can be distinguished based on the ability to produce the anti-inflammatory cytokine IL-10. This part of the proposal stems from our previous work that identified in humans two distinct subsets of IL-10+ and IL-10- Th17 cells that possess different pathogen specificity and have distinct differentiation requirements (Zielinski et al, 2012). A better understanding on the different fates CD4 T cells can adopt will provide insights not only into mechanisms of protection or pathology but also facilitate the development of new therapies. In Aim 3 we will characterize the phenotypes, functional capacities and frequencies of malaria-specific memory CD4+ T cells in volunteers after whole attenuated sporozoite vaccination and controlled human malaria infection. The goal is to identify determinants of cellular malaria-specific immunity in this cohort and to describe correlates of protection or risk from malaria and provide guidance for vaccine design.
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