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Disruption of an Antimycobacterial Circuit Between Dendritic and Helper T Cells in Human SPPL2a Deficiency

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, etc.

Nat Immunol. 2018 Sep;19(9):973-985.

PMID: 30127434

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413185	CD74/DHLAG human			Price

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