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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 T_H1* 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 …