Disruption of an anti-mycobacterial circuit between dendritic and Th cells in human SPPL2a deficiency

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with 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. 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* 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 upon 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 T(H)1* cells.