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

Abstract

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 {zeta} (DGK{zeta}) limits T cell responses through phosphorylation of diacylglycerol into phosphatidic acid. This reaction attenuates diacylglycerol-dependent activation of the Ras/ERK/CD69 and PKC{theta}/NF{kappa}B pathways in response to antigen. Here we show that, in contrast to the lack of basal activation observed in peripheral lymphoid organs, DGK{zeta}-/- mice showed increased numbers of activated T cells in BM, together with a significant increase in IFN{gamma} as well as perforin and granzyme B and C levels. The enhanced presence of T cells in DGK{zeta}-/- 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 DGK{zeta} expression in T cells isolated from the BM of patients with acquired AA, and suggest that limited DGK{zeta} expression and/or functions predispose to T cell-mediated BM destruction. This study identifies the BM as a niche particularly sensitive to DGK{zeta} deficiency and indicates that this mouse model could be of interest for studying the mechanism that contributes to AA development. Key pointsO_LIDGK{zeta}-deficiency in mice results in larger numbers of CD69-positive T cells in bone marrow, with enhanced expression of IFN{gamma} and lytic enzymes. C_LIO_LIDGK{zeta} loss recapitulates many clinical aspects of human aplastic anemia, identifying a critical hub for immune system-dependent bone marrow failure. C_LI Visual abstract O_FIG O_LINKSMALLFIG WIDTH=140 HEIGHT=200 SRC="FIGDIR/small/136390v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@d485b2org.highwire.dtl.DTLVardef@9599c1org.highwire.dtl.DTLVardef@1a17842org.highwire.dtl.DTLVardef@1de640d_HPS_FORMAT_FIGEXP M_FIG C_FIG