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

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 T1* 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 T1* cells.

Engineered niches support the development of human dendritic cells in humanized mice

“…Several protocols have been proposed for the in vitro differentiation of human cDCs from CD34 + HSPCs 7, 38–40, 48, 49 . In vitro differentiated cDC1s have been shown to fully recapitulate both the phenotype and function of circulating bona fide blood cDC1s 8, 39, 48, 49 including high levels of IRF8 expression and Batf3-dependency in vitro 13 , as well as IRF8-dependancy both in vivo 70 and in vit ro 48 . Conversely, several aspects have limited an exhaustive validation of in vitro generated CD1c + cDC2-like cells such as the expression of CD14 7 , the transcriptional alignment with monocyte-derived DCs (moDCs) 39 or the lack of a high-dimensional phenotypic characterization 48, 49 .…”

Insights on the crosstalk between dendritic cells and helper T cells in novel genetic etiology for mendelian susceptible mycobacterial disease

“…1 Although mycobacteria susceptibility-associated genetic mutations are rare in the population, their diagnosis is crucial for an efficient and timely treatment. Kong et al 2 have recently described an autosomal recessive deficiency in the signal peptidase-like 2 A (SPPL2-a) as a new genetic etiology for MSMD in three patients that had suffered BCG dissemination disease.…”

“…This phenotype was reproduced by the treatment of leucocytes derived from healthy donors with SPPL2a inhibitors, also triggered the accumulation of CD74 in mainly HLA Class II + APCs, including B cells and DCs. 2 As SPPL2a is required for B cell development, 7 authors evaluated whether the B cell response was altered in SPPL2a-deficient patients. 2 Importantly, no significant B cell deficiency was evidenced in any of these patients, as compared to healthy controls.…”

“…2 As SPPL2a is required for B cell development, 7 authors evaluated whether the B cell response was altered in SPPL2a-deficient patients. 2 Importantly, no significant B cell deficiency was evidenced in any of these patients, as compared to healthy controls. In this latter study, two out of three patients were twins, which when vaccinated with BCG at birth displayed inflammation at axillary lymph nodes.…”

“…In this latter study, two out of three patients were twins, which when vaccinated with BCG at birth displayed inflammation at axillary lymph nodes. 2 The remaining patient was vaccinated at 2 months of age and presented a left axillary lymphadenopathy. 2 It is worth to mention that the majority of the worldwide population is currently vaccinated with the BCG to prevent from Tuberculosis 8 and that several recombinant BCGs are under development to prevent from viral infections with promising results.…”