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Nat Immunol. 2018 Sep;19(9):973-985. doi: 10.1038/s41590-018-0178-z. Epub 2018 Aug 20.

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

Author information

1
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA.
2
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
3
Center of Medical Immunology, Institute for Research in Biomedicine, Faculty of Biomedical Sciences, University of Italian Switzerland, Bellinzona, Switzerland.
4
Immunology Program, Memorial Sloan Kettering Cancer Center, New York , NY, USA.
5
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
6
St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, New South Wales, Australia.
7
Laboratory of Molecular Immunology, The Rockefeller University, New York , NY, USA.
8
Department of Microbiology and Immunology, Columbia University Medical Center, New York , NY, USA.
9
Laboratory of Clinical Immunology, Inflammation and Allergy, Faculty of Medicine and Pharmacy of Casablanca, King Hassan II University, Casablanca, Morocco.
10
Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Children's Hospital, CHU Averroes, Casablanca, Morocco.
11
Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.
12
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
13
Paris Descartes University, Imagine Institute, Paris, France.
14
La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
15
Study Center for Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France.
16
Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
17
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
18
Department of Pediatric Infectious Diseases and Immunology, Millennium Institute of Immunology and Immunotherapy, School of Medicine, Pontifical Catholic University of Chile, Santiago, Chile.
19
Laboratory of Investigation in Dermatology and Immunodeficiencies, University of Sao Paulo Medical School, Sao Paulo, Brazil.
20
Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.
21
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
22
Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany.
23
Institute of Physiological Chemistry, Technical University Dresden, Dresden, Germany.
24
Howard Hughes Medical Institute, New York, NY, USA.
25
Institute of Microbiology, ETH Zurich, Zürich, Switzerland.
26
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York , NY, USA. casanova@rockefeller.edu.
27
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France. casanova@rockefeller.edu.
28
Paris Descartes University, Imagine Institute, Paris, France. casanova@rockefeller.edu.
29
Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France. casanova@rockefeller.edu.
30
Howard Hughes Medical Institute, New York, NY, USA. casanova@rockefeller.edu.

Abstract

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells.

PMID:
30127434
PMCID:
PMC6130844
[Available on 2019-02-20]
DOI:
10.1038/s41590-018-0178-z

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