Mouse natural killer cell development and maturation are differentially regulated by SHIP-1

Abstract

The SH2-containing inositol phosphatase-1 (SHIP-1) is a 5 inositol phosphatase known to negatively regulate the product of phosphoinositide-3 kinase (PI3K), phosphatidylinositol-3.4,5-trisphosphate. SHIP-1 can be recruited to a large number of inhibitory receptors expressed on natural killer (NK) cells. However, its role in NK cell development, maturation, and functions is not well defined. In this study, we found that the absence of SHIP-1 results in a loss of peripheral NK cells. However, using chimeric mice we demonstrated that SHIP-1 expression is not required intrinsically for NK cell lineage development. In contrast, SHIP-1 is required cell autonomously for NK cell terminal differentiation. These findings reveal both a direct and indirect role for SHIP-1 at different NK cell development checkpoints. Notably, SHIP-1-deficient NK cells display an impaired ability to secrete IFN-␥ during cytokine receptor-mediated responses, whereas immunoreceptor tyrosine-based activation motif containing receptor-mediated responses is not affected. Taken IntroductionNatural killer (NK) cells are large granular lymphocytes with a critical role in innate immunity and are important in orchestrating the adaptive immune system. 1,2 Their ability to produce immunoregulatory cytokines, such as interferon (IFN)-␥, and release perforin and granzymes is crucial for tumor immunosurveillance and elimination of pathogens. 3 These NK effector functions are dependent on the integration of signals delivered from a variety of activating and inhibitory receptors on interaction with neighboring cells. 4 Significant progress has been made on the regulation of receptor and target recognition as well as identification of signals transduced for NK cell action. However, evidence for how these signaling molecules, specifically phosphatases, might govern NK cell development and thereby influence their effector function has been lacking. A better understanding of the mechanisms that govern NK cell development into functional effector cells is crucial to demystifying disease processes and fully utilizing NK cells as therapeutic agents.The bone marrow (BM) is the main site for NK cell development. An intact BM microenvironment provides NK cells with both cellular substrates and signals required from several stromal factors to sustain cell proliferation and differentiation. 1 NK cell precursors (NKPs) in the BM are derived from hematopoietic stem cells that give rise to immature NK (iNK) cells and mature NK (mNK) cells. 5 mNK cells egress from the BM and represent the main NK cell population in the peripheral lymphoid organs, such as the spleen. The NK cell maturation process in the BM has been well characterized based on the differential acquisition of NK cell receptors and the achievement of their full effector functions. 1,6,7 The acquisition of both activating and inhibitory receptors results in the ability of NK cells to recognize and kill target cells with minimal damage to the host. On NK cell synapse formation, appropriate downstream signaling ...

Immune Cell Inhibition by SLAMF7 Is Mediated by a Mechanism Requiring Src Kinases, CD45, and SHIP-1 That Is Defective in Multiple Myeloma Cells

“…2B). In keeping with the involvement of SHIP-1 in multiple inhibitory pathways (15,27,28), this effect was observed whether HeLa cells expressed SLAMF7 or not. Nonetheless, calculation of the extent of inhibition conferred by expression of SLAMF7 on targets showed that SLAMF7-mediated inhibition was attenuated by loss of SHIP-1 (Fig.…”

T-cell Immunoglobulin and ITIM Domain (TIGIT) Receptor/Poliovirus Receptor (PVR) Ligand Engagement Suppresses Interferon-γ Production of Natural Killer Cells via β-Arrestin 2-mediated Negative Signaling

“…SHIP1-deleted mice have severe immune deficiency due to aberrations in the expression of NK cell receptors or downstream signaling (29). A recent study showed that SHIP1 is required for the transition from immature to mature NK cells (39). Generally, hydrolysis of PI(3,4,5)P 3 impairs the recruitment of PH domain-containing kinases to the plasma membrane, resulting in inhibition of PI3K signaling.…”

Inositol tetrakisphosphate limits NK cell effector functions by controlling PI3K signaling

“…4,41,44 A new study suggests that SHIP-1 may control NK cell development and function through combined NK cell-intrinsic and -extrinsic mechanisms. 45 Despite similar Akt hyperactivity in NK cells ( Figure 7C-D), ItpkB Ϫ/Ϫ mice show contrasting reduced mature NK cell numbers, increased NKG2A/C/E/CD94, seemingly unaltered Ly49A, NKG2D, NKp46, and 2B4 but reduced Ly49D/H representation, and the aforementioned hyperactivity and ␥IFN overproduction (Figures 1-7 and supplemental Figures 3-5). It remains to be determined whether these profound differences from SHIP1 Ϫ/Ϫ mice reflect differing increases in cellular PIP 3 activity or impaired specific IP 4 functions unrelated to PIP 3 inhibition 33 in ItpkB Ϫ/Ϫ but not SHIP1 Ϫ/Ϫ NK cells or perturbed positive functions of the SHIP-product PI(3,4)P 2 4,33 in SHIP1 Ϫ/Ϫ but not ItpkB Ϫ/Ϫ NK cells.…”