An Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence

Abstract

We describe a new form of inherited immunodeficiency revealed by an N-ethyl-N-nitrosourea (ENU)-induced mutation called elektra. Homozygotes showed enhanced susceptibility to bacterial and viral infections, and diminished numbers of T cells and inflammatory monocytes that failed to proliferate upon infection and died via the intrinsic apoptotic pathway in response to diverse proliferative stimuli. Elektra mice exhibited an increased proportion of T cells poised to replicate DNA and their T cells expressed a subset of activation markers, suggestive of a semi-activated state. The elektra phenotype was positionally ascribed to a mutation in the gene encoding Schlafen-2 (Slfn2). Our findings reveal a physiological role for Slfn2 in the defense against pathogens through regulation of quiescence in T cells and monocytes.

Expression and Regulatory Effects of Murine Schlafen (Slfn) Genes in Malignant Melanoma and Renal Cell Carcinoma

“…Several mouse Slfn genes, including Slfn1 (4), Slfn 2 (9), and Slfn3 (13, 14, 16) have been shown to play key regula- tory roles in control of cell proliferation and/or differentiation. Mouse Slfn2 has been implicated in immune cell quiescence (10), whereas Slfn4 has been implicated in the control of myelopoiesis (17).…”

“…Slfn2 protein appears to play a role in maintaining quiescence in cells of the immune response, as mice harboring a Slfn2 mutation (elektra) are more susceptible to both bacterial and viral infections, which is a consequence of T cells undergoing apoptosis via the intrinsic pathway (10). More evidence that Slfn2 is involved in the immune response is the observation that this member of the Slfn family is up-regulated by LPS, in an NF-kBand AP-1-dependent manner (6).…”

From mammals to viruses: the Schlafen genes in developmental, proliferative and immune processes

“…Conversely, putative functional redundancy has obscured some results. Such is the case for mouse Slfn1 and Slfn3 knock-outs, for which no apparent phenotype in lymphocytes or monocytes was found (1,49). In contrast, ENUinduced elektra mutation of Slfn2 has provided new insights about the function of this gene.…”

Multiple Players in the Mechanical Control of T Cell Quiescence

“…This increased susceptibility to bacterial and viral infections can be reversed with bacteria artificial chromosome (BAC) transgenesis of Sfln2 gene, thus confirming the role of Sfln2. Interestingly, T cells from eureka mice exist in a semi-activated state [59]. The T cells are generally lesser in amount but express higher surface activation marker (CD44 hi ) and proliferate strongly and are more prone to apoptosis in response to anti-CD3/anti-CD28 activation signal.…”

“…Schlafen proteins promote growth inhibitory responses and play roles in thymocytes development [57], effector, and regulatory T cells [58]. Slfn2 was added to the gaining list of quiescence factors coincidentally when scientists investigate the phenotype in elektra mouse, a G 3 mice homozygous for chemically induced random germline mutation [59]. The eureka mice carry a single mutation in Slfn2, which results in isoleucine-to-asparagine substitution of amino acid residue 135, which is induced after exposure to N-ethyl-N-nitrosourea.…”