Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits-Reference-Cited by-同舟云学术

Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits

Published:2022-06-14 Issue:7 Volume:219 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Whyte Carly E.¹^ORCID,Singh Kailash¹^ORCID,Burton Oliver T.¹²³^ORCID,Aloulou Meryem¹⁴^ORCID,Kouser Lubna¹^ORCID,Veiga Rafael Valente¹^ORCID,Dashwood Amy¹^ORCID,Okkenhaug Hanneke⁵^ORCID,Benadda Samira¹⁶^ORCID,Moudra Alena¹^ORCID,Bricard Orian¹^ORCID,Lienart Stephanie¹^ORCID,Bielefeld Pascal¹^ORCID,Roca Carlos P.¹^ORCID,Naranjo-Galindo Francisco José¹^ORCID,Lombard-Vadnais Félix⁷⁸^ORCID,Junius Steffie²³^ORCID,Bending David⁹^ORCID,Ono Masahiro¹⁰^ORCID,Hochepied Tino¹¹¹²^ORCID,Halim Timotheus Y.F.¹³^ORCID,Schlenner Susan³^ORCID,Lesage Sylvie⁶¹⁴^ORCID,Dooley James¹²³^ORCID,Liston Adrian¹²³^ORCID

Affiliation:

1. Immunology Programme, The Babraham Institute, Cambridge, UK 1

2. VIB Center for Brain and Disease Research, Vlaams Instituut voor Biotechnologie, Leuven, Belgium 2

3. Department of Microbiology, Immunology and Transplantation, KU Leuven—University of Leuven, Leuven, Belgium 3

4. Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Centre national de la recherche scientifique U5051, Institut national de la santé et de la recherche médicale U1291, University of Toulouse III, Toulouse, France 4

5. Imaging Facility, The Babraham Institute, Cambridge, UK 5

6. Centre de Recherche Sur L’inflammation, Centre national de la recherche scientifique ERL8252, Institut national de la santé et de la recherche médicale U1149, Université de Paris, Paris, France 6

7. Department of Microbiology and Immunology, McGill University, Montréal, Quebec, Canada 7

8. Department of Immunology-Oncology, Maisonneuve-Rosemont Hospital, Montréal, Quebec, Canada 8

9. Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK 9

10. Department of Life Sciences, Imperial College London, London, UK 14

11. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium 10

12. VIB Center for Inflammation Research, Vlaams Instituut voor Biotechnologie, Ghent, Belgium 11

13. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK 12

14. Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Quebec, Canada 13

Abstract

Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5–mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.

Funder

Vlaams Instituut voor Biotechnologie

Fonds Wetenschappelijk Onderzoek

European Research Council

Alzheimer’s Association

Medical Research Council

Biotechnology and Biological Sciences Research Council

Vetenskapsrådet

Fondation pour l’Aide à la Recherche sur la Sclérose en Plaques

Imperial College London

Publisher

Rockefeller University Press