[show abstract][hide abstract] ABSTRACT: Lyn kinase, a member of the Src family of tyrosine kinases, functions as both a positive and negative regulator of B cell activation. In the absence of Lyn, BCR signaling is unregulated, leading to perturbed B cell development, hyperactive B cells, and lethal Ab-mediated autoimmune disease. We have generated a mutant mouse pedigree, termed Mld4, harboring a novel mutation in the gene encoding Lyn, which renders the protein devoid of kinase activity. Despite similarities between the phenotypes of Lyn(Mld4/Mld4) and Lyn(-/-) mice, the spectrum of defects in Lyn(Mld4/Mld4) mice is less severe. In particular, although defects in the B cell compartment are similar, splenomegaly, myeloid expansion, and autoantibody production, characteristic of Lyn(-/-) mice, are absent or mild in Lyn(Mld4/Mld4) mice. Critically, immune complex deposition and complement activation in Lyn(Mld4/Mld4) glomeruli do not result in fulminant glomerulonephritis. Our data suggest that BCR hypersensitivity is insufficient for the development of autoimmune disease in Lyn(-/-) mice and implicate other cell lineages, particularly proinflammatory cells, in autoimmune disease progression. Furthermore, our results provide evidence for an additional role for Lyn kinase, distinct from its catalytic activity, in regulating intracellular signaling pathways.
The Journal of Immunology 03/2009; 182(4):2020-9. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Osteoclast inhibitory lectin (OCIL or clrb) is a member of the natural killer cell C-type lectins that have a described role mostly in autoimmune cell function. OCIL was originally identified as an osteoblast-derived inhibitor of osteoclast formation in vitro. To determine the physiological function(s) of OCIL, we generated ocil(-/-) mice. These mice appeared healthy and were fertile, with no apparent immune function defect, and phenotypic abnormalities were limited to bone. Histomorphometric analysis revealed a significantly lower tibial trabecular bone volume and trabecular number in the 10- and 16-week-old male ocil(-/-) mice compared with wild type mice. Furthermore, ocil(-/-) mice showed reduced bone formation rate in the 10-week-old females and 16-week-old males while Static markers of bone formation showed no significant changes in male or female ocil(-/-) mice. Examination of bone resorption markers in the long bones of ocil(-/-) mice indicated a transient increase in osteoclast number per unit bone perimeter. Enhanced osteoclast formation was also observed when either bone marrow or splenic cultures were generated in vitro from ocil(-/-) mice relative to wild type control cultures. Loss of ocil therefore resulted in osteopenia in adult mice primarily as a result of increased osteoclast formation and/or decreased bone formation. The enhanced osteoclastic activity led to elevated serum calcium levels, which resulted in the suppression of circulating parathyroid hormone in 10-week-old ocil(-/-) mice compared with wild type control mice. Collectively, our data suggest that OCIL is a physiological negative regulator of bone.
Journal of Biological Chemistry 10/2008; 283(45):30850-60. · 4.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cytotoxic lymphocytes express a large family of granule serine proteases, including one member, granzyme (Grz)M, with a unique protease activity, restricted expression, and distinct gene locus. Although a number of Grzs, including GrzM, have been shown to mediate target cell apoptosis in the presence of perforin, the biological activity of Grz has been restricted to control of a number of viral pathogens, including two natural mouse pathogens, ectromelia, and murine CMV (MCMV). In this article, we describe the first reported gene targeting of GrzM in mice. GrzM-deficient mice display normal NK cell/T cell development and homeostasis and intact NK cell-mediated cytotoxicity of tumor targets as measured by membrane damage and DNA fragmentation. GrzM-deficient mice demonstrated increased susceptibility to MCMV infection typified by the presence of more viral inclusions and transiently higher viral burden in the visceral organs of GrzM-deficient mice compared with wild-type (WT) mice. The cytotoxicity of NK cells from MCMV-infected GrzM-deficient mice remained unchanged and, like WT control mice, GrzM-deficient mice eventually effectively cleared MCMV infection from the visceral organs. In contrast, GrzM-deficient mice were as resistant as WT control mice to mouse pox ectromelia infection, as well as challenge with a number of NK cell-sensitive tumors. These data confirm a role for GrzM in the host response to MCMV infection, but suggest that GrzM is not critical for NK cell-mediated cytotoxicity.
The Journal of Immunology 10/2005; 175(5):3235-43. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: The CD1d reactive glycolipid, alpha-galactosylceramide (alpha-GalCer), potently activates T cell receptor-alpha type I invariant NKT cells that secondarily stimulate the proliferation and activation of other leukocytes, including NK cells. Here we report a rational approach to improving the antitumor activity of alpha-GalCer by using delayed interleukin (IL)-21 treatment to mature the alpha-GalCer-expanded pool of NK cells into highly cytotoxic effector cells. In a series of experimental and spontaneous metastases models in mice, we demonstrate far superior antitumor activity of the alpha-GalCer/IL-21 combination above either agent alone. Superior antitumor activity was critically dependent upon the increased perforin-mediated cytolytic activity of NK cells. Transfer of alpha-GalCer-pulsed dendritic cells (DCs) followed by systemic IL-21 caused an even more significant reduction in established (day 8) metastatic burden and prolonged survival. In addition, this combination prevented chemical carcinogenesis more effectively. Combinations of IL-21 with other NK cell-activating cytokines, such as IL-2 and IL-12, were much less effective in the same experimental metastases models, and these cytokines did not substitute effectively for IL-21 in combination with alpha-GalCer. Overall, the data suggest that NK cell antitumor function can be enhanced greatly by strategies that are designed to expand and differentiate NK cells via DC activation of NKT cells.
Journal of Experimental Medicine 07/2005; 201(12):1973-85. · 13.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: Natural killer (NK) cells are the primary effector cells of the innate immune system and have a well-established role in tumor rejection in a variety of spontaneous and induced cancer models. NK cell function is regulated by a complex balance of inhibitory and activating signals that allow them to selectively target and kill cells that display an abnormal pattern of cell surface molecules, while leaving normal healthy cells unharmed. In this review we discuss NK cell function, the role of NK cells in cancer therapies, the emerging concept of bi-directional cross-talk between NK cells and dendritic cells, and the implications of these interactions for tumor immunotherapy.
Springer Seminars in Immunopathology 07/2005; 27(1):49-64. · 4.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: Dendritic cells (DC), first characterized in 1973 by Steinman and Cohn, have been defined as the professional antigen presenting cells (APC), capable of activating naïve T cells much more efficiently than either B cells or macrophages. DC also capture and process antigen more efficiently than other APC, and offer MHC-antigen complexes to T cells at higher densities, and in the context of larger amounts of co-stimulatory molecules (i.e. CD40, CD80 and CD86) at the T cell-DC synapse. Although historically, the principal function of DC is the priming of naïve T cells, more recently they have also been shown to affect the functions of natural killer (NK) cells. Interactions between DC and NK cells may be critical in situations where immune surveillance requires efficient early activation of NK cells, as is the case during infections. This review aims to summarise the interactions that occur between DC and NK cells during viral infection.