A critical role for DAP10 and DAP12 in CD8+ T cell–mediated tissue damage in large granular lymphocyte leukemia

Abstract Large granular lymphocyte (LGL) leukemia, or LGLL, is characterized by increased numbers of circulating clonal LGL cells in association with neutropenia, anemia, rheumatoid arthritis, and pulmonary artery hypertension (PAH). Emerging evidence suggests that LGLL cells with a CD8+CD28null phenotype induce these clinical manifestations through direct destruction of normal tissue. Compared with CD8+CD28null T cells from healthy controls, CD8+CD28null T cells from LGLL patients have acquired the ability to directly lyse pulmonary artery endothelial cells and human synovial cells. Here, we show that LGLL cells from patients possess enhanced cytotoxic characteristics and express elevated levels of activating natural killer receptors as well as their signaling partners, DAP10 and DAP12. Moreover, downstream targets of DAP10 and DAP12 are constitutively activated in LGLL cells, and expression of dominant-negative DAP10 and DAP12 dramatically reduces their lytic capacity. These are the first results to show that activating NKR-ligand interactions play a critical role in initiating the DAP10 and DAP12 signaling events that lead to enhanced lytic potential of LGLL cells. Results shown suggest that inhibitors of DAP10 and DAP12 or other proteins involved in this signaling pathway will be attractive therapeutic targets for the treatment of LGLL and other autoimmune diseases and syndromes.

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Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling

Blood ◽

10.1182/blood-2008-02-136382 ◽

2008 ◽

Vol 112 (12) ◽

pp. 4694-4698 ◽

Cited By ~ 31

Author(s):

P. K. Epling-Burnette ◽

Lubomir Sokol ◽

Xianhong Chen ◽

Fanqi Bai ◽

Junmin Zhou ◽

...

Keyword(s):

Pulmonary Artery ◽

Clinical Manifestations ◽

Erythroid Differentiation ◽

Pulmonary Artery Hypertension ◽

Large Granular Lymphocyte ◽

Receptor Signaling ◽

Pulmonary Endothelial Cells ◽

First Case ◽

Nk Receptor ◽

Lgl Leukemia

Abstract Large granular lymphocyte (LGL) leukemia is commonly associated with poor hematopoiesis. The first case of pulmonary artery hypertension (PAH) was observed in a 57-year-old woman with natural killer (NK)–LGL leukemia and transfusion-dependent anemia. Using a genetic approach, we demonstrated that killing of pulmonary endothelial cells by patient NK cells was mediated by dysregulated balance in activating and inhibitory NK-receptor signaling. Elevated pulmonary artery pressure and erythroid differentiation improved after disrupting the NK-receptor signaling pathway with 4 courses of a farnesyltransferase inhibitor, tipifarnib. Coincidental association between PAH and LGL leukemia suggest a causal relationship between the expanded lymphocyte population and these clinical manifestations. This trial is registered at www.ClinicalTrials.gov as NCI 6823.

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Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis

Journal of Experimental Medicine ◽

10.1084/jem.20090545 ◽

2009 ◽

Vol 206 (10) ◽

pp. 2067-2077 ◽

Cited By ~ 258

Author(s):

Soraya Taleb ◽

Mélissa Romain ◽

Bhama Ramkhelawon ◽

Catherine Uyttenhove ◽

Gerard Pasterkamp ◽

...

Keyword(s):

T Cells ◽

Vascular Inflammation ◽

Critical Role ◽

Atherosclerotic Lesion ◽

Dominant Negative ◽

Cytokine Signaling ◽

Interleukin 17 ◽

Macrophage Phenotype ◽

Lesion Development ◽

Regulatory Pathways

Atherosclerosis is an inflammatory vascular disease responsible for the first cause of mortality worldwide. Recent studies have clearly highlighted the critical role of the immunoinflammatory balance in the modulation of disease development and progression. However, the immunoregulatory pathways that control atherosclerosis remain largely unknown. We show that loss of suppressor of cytokine signaling (SOCS) 3 in T cells increases both interleukin (IL)-17 and IL-10 production, induces an antiinflammatory macrophage phenotype, and leads to unexpected IL-17–dependent reduction in lesion development and vascular inflammation. In vivo administration of IL-17 reduces endothelial vascular cell adhesion molecule–1 expression and vascular T cell infiltration, and significantly limits atherosclerotic lesion development. In contrast, overexpression of SOCS3 in T cells reduces IL-17 and accelerates atherosclerosis. We also show that in human lesions, increased levels of signal transducer and activator of transcription (STAT) 3 phosphorylation and IL-17 are associated with a stable plaque phenotype. These results identify novel SOCS3-controlled IL-17 regulatory pathways in atherosclerosis and may have important implications for the understanding of the increased susceptibility to vascular inflammation in patients with dominant-negative STAT3 mutations and defective Th17 cell differentiation.

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TGF-β–dependent CD103 expression by CD8+ T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease

Journal of Experimental Medicine ◽

10.1084/jem.20041044 ◽

2005 ◽

Vol 201 (10) ◽

pp. 1647-1657 ◽

Cited By ~ 157

Author(s):

Riham El-Asady ◽

Rongwen Yuan ◽

Kechang Liu ◽

Donghua Wang ◽

Ronald E. Gress ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Intestinal Epithelium ◽

Critical Role ◽

Dominant Negative ◽

Host Disease ◽

Graft Versus Host ◽

Wide Range

Destruction of the host intestinal epithelium by donor effector T cell populations is a hallmark of graft-versus-host disease (GVHD), but the underlying mechanisms remain obscure. We demonstrate that CD8+ T cells expressing CD103, an integrin conferring specificity for the epithelial ligand E-cadherin, play a critical role in this process. A TCR transgenic GVHD model was used to demonstrate that CD103 is selectively expressed by host-specific CD8+ T cell effector populations (CD8 effectors) that accumulate in the host intestinal epithelium during GVHD. Although host-specific CD8 effectors infiltrated a wide range of host compartments, only those infiltrating the intestinal epithelium expressed CD103. Host-specific CD8 effectors expressing a TGF-β dominant negative type II receptor were defective in CD103 expression on entry into the intestinal epithelium, which indicates local TGF-β activity as a critical regulating factor. Host-specific CD8 effectors deficient in CD103 expression successfully migrated into the host intestinal epithelium but were retained at this site much less efficiently than wild-type host-specific CD8 effectors. The relevance of these events to GVHD pathogenesis is supported by the finding that CD103-deficient CD8+ T cells were strikingly defective in transferring intestinal GVHD pathology and mortality. Collectively, these data document a pivotal role for TGF-β–dependent CD103 expression in dictating the gut tropism, and hence the destructive potential, of CD8+ T cells during GVHD pathogenesis.

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Treatment of Allergic Airway Inflammation and Hyperresponsiveness by Antisense-Induced Local Blockade of Gata-3 Expression

Journal of Experimental Medicine ◽

10.1084/jem.193.11.1247 ◽

2001 ◽

Vol 193 (11) ◽

pp. 1247-1260 ◽

Cited By ~ 163

Author(s):

Susetta Finotto ◽

George T. De Sanctis ◽

Hans A. Lehr ◽

Udo Herz ◽

Michael Buerke ◽

...

Keyword(s):

T Cells ◽

Airway Inflammation ◽

Murine Model ◽

Airway Hyperresponsiveness ◽

Antisense Oligonucleotides ◽

Critical Role ◽

Allergic Airway Inflammation ◽

Dominant Negative ◽

Dna Uptake ◽

Effector Phase

Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA-3 in T cells can prevent T helper cell type 2 (Th2)-mediated allergic airway inflammation in mice. However, it remains unclear whether GATA-3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and/or function of GATA-3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness. Here, we analyzed the effects of locally antagonizing GATA-3 function in a murine model of asthma. We could suppress GATA-3 expression in interleukin (IL)-4–producing T cells in vitro and in vivo by an antisense phosphorothioate oligonucleotide overlapping the translation start site of GATA-3, whereas nonsense control oligonucleotides were virtually inactive. In a murine model of asthma associated with allergic pulmonary inflammation and hyperresponsiveness in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate–labeled GATA-3 antisense oligonucleotides led to DNA uptake in lung cells associated with a reduction of intracellular GATA-3 expression. Such intrapulmonary blockade of GATA-3 expression caused an abrogation of signs of lung inflammation including infiltration of eosinophils and Th2 cytokine production. Furthermore, treatment with antisense but not nonsense oligonucleotides induced a significant reduction of airway hyperresponsiveness in OVA-sensitized mice to levels comparable to saline-treated control mice, as assessed by both enhanced pause (PenH) responses and pulmonary resistance determined by body plethysmography. These data indicate a critical role for GATA-3 in the effector phase of a murine asthma model and suggest that local delivery of GATA-3 antisense oligonucleotides may be a novel approach for the treatment of airway hyperresponsiveness such as in asthma. This approach has the potential advantage of suppressing the expression of various proinflammatory Th2 cytokines simultaneously rather than suppressing the activity of a single cytokine.

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Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells

Journal of Experimental Medicine ◽

10.1084/jem.20190678 ◽

2019 ◽

Vol 216 (12) ◽

pp. 2800-2818 ◽

Cited By ~ 18

Author(s):

Rémy Rodriguez ◽

Benjamin Fournier ◽

Debora Jorge Cordeiro ◽

Sarah Winter ◽

Kazushi Izawa ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Epstein Barr Virus ◽

Critical Role ◽

Costimulatory Molecule ◽

Clinical Manifestations ◽

Calcium Flux ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Epstein Barr

Infection of T cells by Epstein-Barr virus (EBV) causes chronic active EBV infection (CAEBV) characterized by T cell lymphoproliferative disorders (T-LPD) of unclear etiology. Here, we identified two homozygous biallelic loss-of-function mutations in PIK3CD and TNFRSF9 in a patient who developed a fatal CAEBV. The mutation in TNFRSF9 gene coding CD137/4-1BB, a costimulatory molecule expressed by antigen-specific activated T cells, resulted in a complete loss of CD137 expression and impaired T cell expansion toward CD137 ligand–expressing cells. Isolated as observed in one sibling, CD137 deficiency resulted in persistent EBV-infected T cells but without clinical manifestations. The mutation in PIK3CD gene that encodes the catalytic subunit p110δ of the PI3K significantly reduced its kinase activity. Deficient T cells for PIK3CD exhibited reduced AKT signaling, while calcium flux, RAS-MAPK activation, and proliferation were increased, suggestive of an imbalance between the PLCγ1 and PI3K pathways. These skewed signals in T cells may sustain accumulation of EBV-infected T cells, a process controlled by the CD137–CD137L pathway, highlighting its critical role in immunity to EBV.

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STAT3 Signaling in Donor-Derived CD4+ T-Cells Plays a Critical Role in the Induction of Acute and Chronic GVHD in Murine Models of alloBMT.

Blood ◽

10.1182/blood.v110.11.2179.2179 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2179-2179

Author(s):

Vedran Radojcic ◽

Maria A. Pletneva ◽

Hung-Rong Yen ◽

Timothy J. Harris ◽

Drew M. Pardoll ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Chronic Gvhd ◽

Critical Role ◽

Clinical Signs ◽

Clinical Manifestations ◽

Murine Models ◽

Wild Type ◽

Stat3 Signaling

Abstract Growing evidence from several murine models suggests that STAT3 signaling in CD4+ T-cells plays a pivotal role in the pathogenesis of autoimmunity. We herein tested the hypothesis that the same pathway plays a critical role in the induction of GVHD in murine models of allogeneic BMT. To test our hypothesis and to compare the differential ability of STAT3 signaling in CD4+ T-cells to mediate GVHD in MHC-mismatched and-matched murine models of alloBMT, CD4-Cre × STAT3flox/flox (STAT3KOCD4+), or corresponding wild-type control mice were used as donors of CD4+ T-cells. In an MHC-mismatched model, groups of lethally irradiated (775 cGy) BALB/c (H-2d) mice received T-cell depleted (TCD) bone marrow (BM) from wild-type C57BL/6 (H-2b) mice alone, TCD B6 BM plus 4 × 105wild-type, or STAT3KOCD4+ T-cells, all on a C57BL/6 background. In repeated experiments we observed significantly decreased clinical signs of GVHD in animals receiving STAT3KOCD4+ in comparison to those receiving wild-type CD4+ T-cells (median GVHD score of 2.25 vs. 5.29; P <.001) but no difference in lethality in chimeras monitored up to day 60 posttransplant. In an MHC-matched, minor histocompatibility mismatched setting, we conducted experiments using the B10.D2 (H-2d) BALB/c (H-2d) model in which GVHD is CD4+ T-cell-mediated and has clinicopathologic consistent with human chronic GVHD. Since the dominant clinical manifestation in this model is cutaneous sclerodermatous GVHD that is associated with in situ dermal mononuclear infiltrates, the use of BALB/c-CD45.1 (CD45.1+) mice as recipients enabled us to examine the fate of skin CD11c+ dendritic cells. After conditioning (775 cGy) recipient mice received B10.D2 (CD45.2+) TCD BM and 9.3 ×106 TCD splenocytes, repleted with 106 wild-type CD8+ and 1.9 ×106 wild-type, or STAT3KOCD4+ T-cells. We reproducibly induced all signs of chronic GVHD in chimeras receiving wild-type CD4+ T-cells, but not in chimeras injected with STAT3KOCD4+ T-cells (median GVHD score of 5.2 vs. 0.0; P <.001). We found that development of cutaneous GVHD was accompanied by prominent dermal infiltration of donor-derived inflammatory monocytes and complete turnover to donor CD11c+ epidermal DC chimerism (88.4±4.3% vs. 0.9±0.6%; P <.001). Interestingly, splenic CD11c+ DC (99.9±0.1% vs. 99.8±0.1%), CD4+ (99.9±0.2% vs. 99.6±0.7%) and CD8+ (99.9±0.2% vs. 99.9±0.2%) T-cell chimerism was nearly completely donor-derived and did not differ between the two sets of described chimeras. In summary, our data suggest that intact STAT3 signaling in CD4+ T-cells is required for clinical manifestations of delayed acute and/or chronic GVHD, but it does not interfere with lymphohematopoietic graft-versus host response and achievement of full donor chimerism. Further exploration of the STAT3 signaling pathway in pathophysiology of delayed acute and/or chronic GVHD is warranted.

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Critical role for Rsk2 in T-lymphocyte activation

Blood ◽

10.1182/blood-2007-02-072207 ◽

2008 ◽

Vol 111 (2) ◽

pp. 525-533 ◽

Cited By ~ 27

Author(s):

Jian-Xin Lin ◽

Rosanne Spolski ◽

Warren J. Leonard

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cellular Response ◽

Cell Activation ◽

Critical Role ◽

Interleukin 2 ◽

Dominant Negative ◽

Mitogen Activated Protein Kinase ◽

Wild Type

During T-cell activation, a number of cytokine-activated signaling cascades, including the Jak-STAT, phosphoinositol 3-kinase (PI 3-kinase), and mitogen-activated protein kinase (MAPK) pathways, play important roles in modulating the expression of target genes and mediating a cellular response. We now report that interleukin 2 (IL-2) and IL-15, but not IL-7, rapidly activate the p90 ribosomal S6 kinases, Rsk1 and Rsk2, in human T lymphocytes. Surprisingly, mouse spleen T cells transduced with either the wild-type or a dominant-negative (DN) Rsk2-expressing retrovirus could not be recovered, in contrast to the normal survival of T cells transduced with retroviruses expressing wild-type or DN mutants of Rsk1 or Rsk3. Examination of Rsk2 knockout (KO) mice revealed normal T-cell development, but these T cells had delayed cell-cycle progression and lower production of IL-2 in response to anti-CD3 and anti-CD28 stimulation in vitro. Moreover, Rsk2 KO mice had defective homeostatic T-cell expansion following sublethal irradiation in vivo, which is known to involve T-cell receptor (TCR), IL-2, and/or IL-15 signals, each of which we demonstrate can rapidly and potently activate Rsk2 in mouse T cells. These results indicate an essential nonredundant role of Rsk2 in T-cell activation.

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Association between RNF213 c.14576G>A Variant (rs112735431) and Peripheral Pulmonary Artery Stenosis in Moyamoya Disease

Cerebrovascular Diseases ◽

10.1159/000519717 ◽

2021 ◽

pp. 1-6

Author(s):

Dan Ozaki ◽

Hidenori Endo ◽

Ryosuke Tashiro ◽

Koichiro Sugimura ◽

Shunsuke Tatebe ◽

...

Keyword(s):

Pulmonary Artery ◽

Moyamoya Disease ◽

Clinical Manifestations ◽

Pulmonary Artery Hypertension ◽

Artery Stenosis ◽

Vascular Lesions ◽

Pulmonary Artery Stenosis ◽

Surgical Indications ◽

Retrospective Case ◽

Predisposing Factor

Background: Moyamoya disease (MMD) and peripheral pulmonary artery stenosis (PPAS) are relatively rare and demonstrate steno-occlusive vascular lesions in different organs. Genetic studies identified RNF213 polymorphism c.14576G>A (rs112735431) as a susceptibility variant for East Asian MMD. RNF213 polymorphism c.14576G>A is further associated with various vascular lesions of other organs. In this study, we aimed to clarify the incidence and clinical manifestations of PPAS in MMD patients and analyze the correlation between RNF213 genotype and PPAS. Methods: This retrospective case-control study investigated the association between RNF213 polymorphism and PPAS in 306 MMD/quasi-MMD patients, reviewing the medical charts and imaging records of consecutive patients with MMD admitted from January 2015 to December 2020. Results: PPAS was observed in 3 MMD/quasi-MMD patients (0.98%, 3/306). RNF213 polymorphism c.14576G>A was determined for all 306 MMD/quasi-MMD patients. The incidence of PPAS in RNF213-wildtype, RNF213-heterozygote, and RNF213-homozygote MMD/quasi-MMD patients was 0% (0/101), 0.5% (1/200), and 40% (2/5), respectively. The association between PPAS and homozygote polymorphism of RNF213 c.14576G>A was statistically significant in MMD/quasi-MMD patients (p = 0.0018). In all cases, pulmonary artery hypertension due to PPAS was evident during their childhood and young adolescent stages. Surgical indications for MMD were discouraged in 1 case due to her severe cardiopulmonary dysfunction. Conclusions: The homozygote variant of RNF213 polymorphism c.14576G>A can be a potential predisposing factor for PPAS in MMD/quasi-MMD patients. Despite the relatively rare entity, PPAS should be noted to determine surgical indications for MMD/quasi-MMD patients.

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