Differential expression of SHIP1 in CD56bright and CD56dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation

Trotta, Rossana; Parihar, Robin; Yu, Jianhua; Becknell, Brian; Allard, Jeffrey; Wen, Jing; Ding, Wei; Mao, Hsiaoyin; Tridandapani, Susheela; Carson, William E.; Caligiuri, Michael A.

doi:10.1182/blood-2004-10-4072

Cited by 69 publications

(87 citation statements)

References 56 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CD56 bright NK cells have been labeled ''immunoregulatory'' based on their ability to secrete cytokines (20) and home to lymph nodes (21) and tissues (22) and their expansion in humans during states characterized by increased immune tolerance (23, 24) such as pregnancy. Animal studies demonstrated a regulatory role of NK cells in autoimmunity in general (25)(26)(27)(28), and in particular in experimental autoimmune encephalomyelitis (EAE) (25,27), the animal model of MS.…”

Section: Discussionmentioning

confidence: 99%

Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Bielekova

Catálfamo

Reichert-Scrivner

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

560

543

View full text Add to dashboard Cite

Administration of daclizumab, a humanized mAb directed against the IL-2R␣ chain, strongly reduces brain inflammation in multiple sclerosis patients. Here we show that daclizumab treatment leads to only a mild functional blockade of CD4 ؉ T cells, the major candidate in multiple sclerosis pathogenesis. Instead, daclizumab therapy was associated with a gradual decline in circulating CD4 ؉ and CD8 ؉ T cells and significant expansion of CD56 bright natural killer (NK) cells in vivo, and this effect correlated highly with the treatment response. In vitro studies showed that NK cells inhibited T cell survival in activated peripheral blood mononuclear cell cultures by a contact-dependent mechanism. Positive correlations between expansion of CD56 bright NK cells and contraction of CD4 ؉ and CD8 ؉ T cell numbers in individual patients in vivo provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during daclizumab therapy. Our data support the existence of an immunoregulatory pathway wherein activated CD56 bright NK cells inhibit T cell survival. This immunoregulation has potential importance for the treatment of autoimmune diseases and transplant rejection and toward modification of tumor immunity.CD25 ͉ IL-2 ͉ immunoregulatory natural killer cells M ultiple sclerosis (MS) is an inflammatory͞demyelinating disease of the CNS that is one of the leading causes of neurological disability in young adults (1). It is believed that MS is a T cell-mediated autoimmune disease, and therefore the search for new therapies focuses on agents that affect lymphocyte function. Daclizumab (Zenapax), a humanized mAb that blocks the IL-2 binding site on the IL-2R␣ chain, CD25 (i.e., Tac epitope), is among these novel agents (2). The IL-2R complex is comprised of three subunits: IL-2R␣ (CD25), IL-2R␤ (CD122), and IL-2R␥ (CD132). CD122 and CD132 have intracellular signaling motifs and together form the intermediate-affinity (K dis Ϸ 0.1-1 nM) IL-2R. CD25 binds IL-2 with low (K dis Ϸ 10 nM) affinity, but when it associates with CD122͞CD132 it stabilizes the complex to form the highaffinity (K dis Ϸ 10 pM) receptor (3). CD25 is present at low levels in resting human T cells (with the exception of T regulatory cells) but is significantly up-regulated on activated T cells, enabling them to receive a high-affinity IL-2 signal (4). Therefore, it is believed that the blockade of CD25 will result in selective functional inhibition of activated T cells (5). Although it has been demonstrated that daclizumab (or the original murine anti-Tac mAb) inhibits early IL-2R signal transduction events (6, 7) and blocks T cell activation and expansion in vitro (8), a comprehensive characterization of its in vivo effects is still lacking.We recently concluded a phase II, open-label, baseline-versustreatment crossover trial of daclizumab in 10 MS patients with incomplete therapeutic response to IFN-␤. Daclizumab showed a profound inhibitory effect on brain inflammatory activity (78% reduction) and subsequent stabilization o...

show abstract

Section: Discussionmentioning

confidence: 99%

Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Bielekova

Catálfamo

Reichert-Scrivner

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

560

543

View full text Add to dashboard Cite

show abstract

“…SHIP is expressed predominantly by cells in the hematopoietic compartment (Kerr 2011). SHIP it is also found to be present in osteoblasts, mature granulocytes, monocyte/macrophages, mast cells, platelets and NK cells (Cox et al 2001;Geier et al 1997;Giuriato et al 1997;Hazen et al 2009;Maresco et al 1999;Trotta et al 2005).…”

Section: Inpp5dmentioning

confidence: 99%

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Zhang

et al. 2015

Arch. Immunol. Ther. Exp.

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a complex agerelated neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE e4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

show abstract

“…Isolation of fresh human primary NK cells from peripheral blood (American Red Cross, Columbus, OH), in accordance with The Ohio State University Institutional Review Board, has been previously described [21,43]. The amphotropic-packaging cell line Phoenix (a generous gift of Dr. G. P. Nolan, Stanford University, Stanford, CA) was maintained in culture in DMEM (Invitrogen) medium containing 10% FBS and grown for 16-18 h to 80% confluency prior to transfection by calcium phosphate-DNA precipitation methods (Promega, Madison, WI).…”

Section: Cell Lines Cell Culture and Isolation Of Primary Nk Cellsmentioning

confidence: 99%

Transcriptional control of human T‐BET expression: The role of Sp1

Min

Boyd

et al. 2007

Eur J Immunol

View full text Add to dashboard Cite

Murine T-bet (T-box expressed in T cells) is a master regulator of IFN-c gene expressionin NK and T cells. T-bet also plays a critical role in autoimmunity, asthma and other diseases. However, cis elements or trans factors responsible for regulating T-bet expression remain largely unknown. Here, we report on our discovery of six Sp1-binding sites within the proximal human T-BET promoter that are highly conserved among mammalian species. Electrophoretic mobility shift assays demonstrate a physical association between Sp1 and the proximal T-BET promoter with a direct dose response between Sp1 expression and T-BET promoter activity. Ectopic overexpression of Sp1 also enhanced T-BET expression and cytokine-induced IFN-c secretion in NK cells and T cells. Mithramycin A, which blocks the binding of Sp1 to the T-BET promoter, diminished both T-BET expression and IFN-c protein production in monokine-stimulated primary human NK cells. Collectively, our results suggest that Sp1 is a positive transcriptional regulator of T-BET. As T-BET and IFN-c are critically important in inflammation, infection, and cancer, targeting Sp1, possibly with mithramycin A, may be useful for preventing and/ or treating diseases associated with aberrant T-BET or IFN-c expression.

show abstract

Differential expression of SHIP1 in CD56bright and CD56dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation

Cited by 69 publications

References 56 publications

Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Transcriptional control of human T‐BET expression: The role of Sp1

Contact Info

Product

Resources

About

Differential expression of SHIP1 in CD56bright and CD56dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation

Cited by 69 publications

References 56 publications

Regulatory CD56brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Regulatory CD56brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Transcriptional control of human T‐BET expression: The role of Sp1

Contact Info

Product

Resources

About

Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

Regulatory CD56^brightnatural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis