Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
Xiao-Fei KongRuben Martinez-BarricarteJames KennedyFederico MeleTomi LazarovElissa K DeenickCindy S MaGaëlle BretonKimberly B LuceroDavid LanglaisAziz BousfihaCaner AytekinJanet MarkleCéline TrouilletFabienne Jabot-HaninCecilia S Lindestam ArlehamnGeetha RaoCapucine PicardThéo LasseauDaniela LatorreSophie HambletonCaroline DeswarteYuval ItanKatia AbarcaDewton Moraes-VasconcelosFatima AilalAydan IkinciogullariFigen DoguIbtihal BenhsaienAlessandro SetteLaurent AbelStéphanie Boisson-DupuisBernd SchröderMichel C NussenzweigKang LiuFrederic GeissmannStuart G TangyePhilippe GrosFederica SallustoJacinta BustamanteJean Laurent CasanovaPublished in: Nature immunology (2018)
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.
Keyphrases
- dendritic cells
- mycobacterium tuberculosis
- induced apoptosis
- immune response
- cell cycle arrest
- endothelial cells
- endoplasmic reticulum stress
- signaling pathway
- oxidative stress
- end stage renal disease
- metabolic syndrome
- dna methylation
- cell proliferation
- working memory
- bone marrow
- chronic kidney disease
- skeletal muscle
- type diabetes
- patient reported outcomes
- patient safety
- copy number
- adipose tissue
- genome wide
- insulin resistance