Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

Abstract

Key points• DGKζ-deficiency in mice results in larger numbers of CD69-positive T cells in bone marrow, with enhanced expression of IFNγ and lytic enzymes.• DGKζ loss recapitulates many clinical aspects of human aplastic anemia, identifying a critical hub for immune system-dependent bone marrow failure. Visual abstractAbstract Acquired aplastic anemia (AA) is a rare blood disorder that results from immune-mediated destruction of bone marrow (BM) progenitor cells. Improved understanding of the mechanisms that favor T cell attack in BM could help to improve early diagnosis and disease treatment. Diacylglycerol kinase ζ (DGKζ) limits T cell responses through phosphorylation of diacylglycerol into phosphatidic acid. This reaction attenuates diacylglycerol-dependent activation of the Ras/ERK/CD69 and PKCθ/NFκB pathways in response to antigen. Here we show that, in contrast to the lack of basal activation observed in peripheral lymphoid organs, DGKζ -/mice showed increased numbers of activated T cells in BM, together with a significant increase in IFNγ as well as perforin and granzyme B and C levels. The enhanced presence of T cells in DGKζ -/mouse BM correlates with reduced BM cellularity, impaired hematopoiesis, and lower frequency of circulating red cells, granulocytes, and platelets. Our studies coincide with the recent characterization of lower DGKζ expression in T cells isolated from the BM of patients with acquired AA, and suggest that limited DGKζ expression and/or functions predispose to T cell-mediated BM destruction. This study identifies the BM as a niche particularly sensitive to DGKζ deficiency and indicates that this mouse model could be of interest for studying the mechanism that contributes to AA development.