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Profiling MHC II immunopeptidome of blood-stage malaria reveals that cDC1 control the functionality of parasite-specific CD4 T cells.

Authors
  • Draheim, Marion1
  • Wlodarczyk, Myriam F1
  • Crozat, Karine2
  • Saliou, Jean-Michel3, 4
  • Alayi, Tchilabalo Dilezitoko3, 4
  • Tomavo, Stanislas3, 4
  • Hassan, Ali1
  • Salvioni, Anna1
  • Demarta-Gatsi, Claudia5
  • Sidney, John6
  • Sette, Alessandro6
  • Dalod, Marc2
  • Berry, Antoine1
  • Silvie, Olivier7
  • Blanchard, Nicolas8
  • 1 Centre de Physiopathologie Toulouse Purpan (CPTP), INSERM, CNRS, Université de Toulouse, UPS, Toulouse, France. , (France)
  • 2 CNRS, INSERM, CIML, Aix Marseille Université, Marseille, France. , (France)
  • 3 Centre d'Infection et d'Immunité de Lille (CIIL), CNRS UMR 8204, Inserm U1019, CHU Lille, Institut Pasteur de Lille, University of Lille, Lille, France. , (France)
  • 4 Plateforme de Protéomique et Peptides Modifiés (P3M), CNRS, Institut Pasteur de Lille, University of Lille, Lille, France. , (France)
  • 5 CNRS, INSERM, Institut Pasteur, Unité de Biologie des Interactions Hôte Parasites, Paris, France. , (France)
  • 6 La Jolla Institute of Allergy and Immunology, San Diego, CA, USA.
  • 7 INSERM, CNRS, Centre d'Immunologie et des Maladies Infectieuses, Sorbonne Universités, UPMC University of Paris 06, Paris, France. , (France)
  • 8 Centre de Physiopathologie Toulouse Purpan (CPTP), INSERM, CNRS, Université de Toulouse, UPS, Toulouse, France [email protected] , (France)
Type
Published Article
Journal
EMBO Molecular Medicine
Publisher
EMBO
Publication Date
Nov 01, 2017
Volume
9
Issue
11
Pages
1605–1621
Identifiers
DOI: 10.15252/emmm.201708123
PMID: 28935714
Source
Medline
Keywords
License
Unknown

Abstract

In malaria, CD4 Th1 and T follicular helper (TFH) cells are important for controlling parasite growth, but Th1 cells also contribute to immunopathology. Moreover, various regulatory CD4 T-cell subsets are critical to hamper pathology. Yet the antigen-presenting cells controlling Th functionality, as well as the antigens recognized by CD4 T cells, are largely unknown. Here, we characterize the MHC II immunopeptidome presented by DC during blood-stage malaria in mice. We establish the immunodominance hierarchy of 14 MHC II ligands derived from conserved parasite proteins. Immunodominance is shaped differently whether blood stage is preceded or not by liver stage, but the same ETRAMP-specific dominant response develops in both contexts. In naïve mice and at the onset of cerebral malaria, CD8α+ dendritic cells (cDC1) are superior to other DC subsets for MHC II presentation of the ETRAMP epitope. Using in vivo depletion of cDC1, we show that cDC1 promote parasite-specific Th1 cells and inhibit the development of IL-10+ CD4 T cells. This work profiles the P. berghei blood-stage MHC II immunopeptidome, highlights the potency of cDC1 to present malaria antigens on MHC II, and reveals a major role for cDC1 in regulating malaria-specific CD4 T-cell responses.

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