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

Xiao Fei Kong, Ruben Martinez-Barricarte, James Kennedy, Federico Mele, Tomi Lazarov, Elissa K. Deenick, Cindy S. Ma, Gaëlle Breton, Kimberly B. Lucero, David Langlais, Aziz Bousfiha, Caner Aytekin, Janet Markle, Céline Trouillet, Fabienne Jabot-Hanin, Cecilia S.Lindestam Arlehamn, Geetha Rao, Capucine Picard, Théo Lasseau, Daniela LatorreSophie Hambleton, Caroline Deswarte, Yuval Itan, Katia Abarca, Dewton Moraes-Vasconcelos, Fatima Ailal, Aydan Ikinciogullari, Figen Dogu, Ibtihal Benhsaien, Alessandro Sette, Laurent Abel, Stéphanie Boisson-Dupuis, Bernd Schröder, Michel C. Nussenzweig, Kang Liu, Frédéric Geissmann, Stuart G. Tangye, Philippe Gros, Federica Sallusto, Jacinta Bustamante, Jean Laurent Casanova

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)973-985
Number of pages13
JournalNature immunology
Issue number9
StatePublished - Sep 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


Dive into the research topics of 'Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency'. Together they form a unique fingerprint.

Cite this