TY - JOUR
T1 - Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency
AU - Kong, Xiao Fei
AU - Martinez-Barricarte, Ruben
AU - Kennedy, James
AU - Mele, Federico
AU - Lazarov, Tomi
AU - Deenick, Elissa K.
AU - Ma, Cindy S.
AU - Breton, Gaëlle
AU - Lucero, Kimberly B.
AU - Langlais, David
AU - Bousfiha, Aziz
AU - Aytekin, Caner
AU - Markle, Janet
AU - Trouillet, Céline
AU - Jabot-Hanin, Fabienne
AU - Arlehamn, Cecilia S.Lindestam
AU - Rao, Geetha
AU - Picard, Capucine
AU - Lasseau, Théo
AU - Latorre, Daniela
AU - Hambleton, Sophie
AU - Deswarte, Caroline
AU - Itan, Yuval
AU - Abarca, Katia
AU - Moraes-Vasconcelos, Dewton
AU - Ailal, Fatima
AU - Ikinciogullari, Aydan
AU - Dogu, Figen
AU - Benhsaien, Ibtihal
AU - Sette, Alessandro
AU - Abel, Laurent
AU - Boisson-Dupuis, Stéphanie
AU - Schröder, Bernd
AU - Nussenzweig, Michel C.
AU - Liu, Kang
AU - Geissmann, Frédéric
AU - Tangye, Stuart G.
AU - Gros, Philippe
AU - Sallusto, Federica
AU - Bustamante, Jacinta
AU - Casanova, Jean Laurent
N1 - Funding Information:
We thank B. Coller, C. Rice, X. Ma, M. Ciancanelli, and G. Vogt for helpful discussions and critical reading. We thank Y. Nemirovskaya, E. Anderson, T. Kochetkov, M. Romanick, L. Amar, C. Patissier, C. Desvallées, M. Woollett, D. Papandrea, A. Gall, and J. Gonzalez for technical and secretarial assistance, and all members of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions. We thank F. Batteux and M. Bahuad from the Laboratory of Immunology, Cochin Hospital, Paris, France, for serological testing of patients, and F. B. Menozzi and the rest of the Microbiology Institute, EOC, Bellinzona, for providing microbial products. X.-F.K. was supported by the Jerome Lejeune Foundation, the Stony Wold-Herbert Fund, the Choh-Hao Li Memorial Fund Scholar Award, and the Shanghai Educational Development Foundation. R.M.B. was funded by a European Molecular Biology Organization (EMBO) long-term fellowship. J.M. was supported by the Charles H. Revson Senior Fellowship in Biomedical Sciences. B.S. received support from the Deutsche Forschungsgemeinschaft as part of the SFB877 and the Cluster of Excellence ‘Inflammation at Interfaces’, and the SCHR 1284/1-1 grant. The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the St. Giles Foundation (J.-L.C.), The Rockefeller University Center for Clinical and Translational Science (grant UL1TR001866 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS) to R.M.-B. and X.-F.K.), the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (5R01AI089970-02 and 5R37AI095983 to J.-L.C.), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID, and the French National Research Agency (ANR) under the ‘Investments for the future’ program (ANR-10-IAHU-01 to L.A.), ANR-IFNGPHOX (ANR-13-ISV3-0001-01, to J.B.), and ANR-GENMSMD (ANR-16-CE17-0005-01, to J.B.), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, and The Rockefeller University. E.K.D., C.S.M., and S.G.T. are supported by research grants and fellowships from the National Health and Medical Research Council of Australia. D.L. was supported by a fellowship from the Fonds de Recherche du Québec Santé. Work in P.G.’s laboratory was supported by a grant from the National Institute of Allergy and Infectious Diseases (R01AI035237-19). The work at the Institute for Research in Biomedicine was supported by grants from the ERC (323183 PREDICT, to F.S.), the Swiss National Science Foundation (170213, to F.S.), and the Helmut Horten Foundation. This work was supported by award U19AI118626, NIH NIAID (to A.S. and F.S.).
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41590-018-0178-z
DO - 10.1038/s41590-018-0178-z
M3 - Article
C2 - 30127434
AN - SCOPUS:85051985294
SN - 1529-2908
VL - 19
SP - 973
EP - 985
JO - Nature Immunology
JF - Nature Immunology
IS - 9
ER -