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

作者：Kong Xiao Fei; Martinez Barricarte Ruben; Kennedy James; Mele Federico; Lazarov Tomi; Deenick Elissa K; Ma Cindy S; Breton Gaelle; Lucero Kimberly B; Langlais David; Bousfiha Aziz; Aytekin Caner; Markle Janet; Trouillet Celine; Jabot Hanin Fabienne; Arlehamn Cecilia S Lindestam; Rao Geetha; Picard Capucine; Lasseau Theo; Latorre Daniela; Hambleton Sophie; Deswarte Caroline; Itan Yuval; Abarca Katia; Moraes Vasconcelos Dewton; Ailal Fatima; Ikinciogullari Aydan

来源：Nature Immunology, 2018, 19(9): 973-+.

DOI：10.1038/s41590-018-0178-z

Human inborn errors of IFN-gamma 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 T(H)1(star) cells selectively fail to produce IFN-gamma when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a(-/-) mice lack cDC2s, have CD4(+) T cells that produce small amounts of IFN-gamma 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-gamma production by mycobacterium-specific memory T(H)1(star) cells.

• 出版日期2018-9
• 单位McGill