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1.
Front Oncol ; 11: 662723, 2021.
Article in English | MEDLINE | ID: mdl-35223446

ABSTRACT

Myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) contribute to cancer-related inflammation and tumor progression. While several myeloid molecules have been ascribed a regulatory function in these processes, the triggering receptors expressed on myeloid cells (TREMs) have emerged as potent modulators of the innate immune response. While various TREMs amplify inflammation, others dampen it and are emerging as important players in modulating tumor progression-for instance, soluble TREM-1 (sTREM-1), which is detected during inflammation, associates with disease progression, while TREM-2 expression is associated with tumor-promoting macrophages. We hypothesized that TREM-1 and TREM-2 might be co-expressed on tumor-infiltrating myeloid cells and that elevated sTREM-1 associates with disease outcomes, thus representing a possibility for mutual modulation in cancer. Using the 4T1 breast cancer model, we found TREM-1 and TREM-2 expression on MDSC and TAM and that sTREM-1 was elevated in tumor-bearing mice in multiple models and correlated with tumor volume. While TREM-1 engagement enhanced TNF, a TREM-2 ligand was detected on MDSC and TAM, suggesting that both TREM could be functional in the tumor setting. Similarly, we detected TREM-1 and Trem2 expression in myeloid cells in the RENCA model of renal cell carcinoma (RCC). We confirmed these findings in human disease by demonstrating the expression of TREM-1 on tumor-infiltrating myeloid cells from patients with RCC and finding that sTREM-1 was increased in patients with RCC. Finally, The Cancer Genome Atlas analysis shows that TREM1 expression in tumors correlates with poor outcomes in RCC. Taken together, our data suggest that manipulation of the TREM-1/TREM-2 balance in tumors may be a novel means to modulate tumor-infiltrating myeloid cell phenotype and function.

2.
PLoS Pathog ; 9(5): e1003357, 2013 May.
Article in English | MEDLINE | ID: mdl-23675302

ABSTRACT

Fungal pathogens elicit cytokine responses downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled or hemiITAM-containing receptors and TLRs. The Linker for Activation of B cells/Non-T cell Activating Linker (LAB/NTAL) encoded by Lat2, is a known regulator of ITAM-coupled receptors and TLR-associated cytokine responses. Here we demonstrate that LAB is involved in anti-fungal immunity. We show that Lat2-/- mice are more susceptible to C. albicans infection than wild type (WT) mice. Dendritic cells (DCs) express LAB and we show that it is basally phosphorylated by the growth factor M-CSF or following engagement of Dectin-2, but not Dectin-1. Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear ß-catenin levels. This in turn is important for controlling fungal/PAMP-induced cytokine production in DCs. C. albicans- and LPS-induced IL-12 and IL-23 production was blunted in Lat2-/- DCs. Accordingly, Lat2-/- DCs directed reduced Th1 polarization in vitro and Lat2-/- mice displayed reduced Natural Killer (NK) and T cell-mediated IFN-γ production in vivo/ex vivo. Thus our data define a novel link between LAB and ß-catenin nuclear accumulation in DCs that facilitates IFN-γ responses during anti-fungal immunity. In addition, these findings are likely to be relevant to other infectious diseases that require IL-12 family cytokines and an IFN-γ response for pathogen clearance.


Subject(s)
Amino Acid Transport System y+/immunology , Candidiasis/immunology , Dendritic Cells/immunology , Fusion Regulatory Protein 1, Light Chains/immunology , Lectins, C-Type/immunology , beta Catenin/immunology , Amino Acid Transport System y+/metabolism , Animals , Candidiasis/metabolism , Dendritic Cells/metabolism , Disease Models, Animal , Female , Fusion Regulatory Protein 1, Light Chains/metabolism , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Interleukin-12/biosynthesis , Interleukin-12/immunology , Lectins, C-Type/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/immunology , beta Catenin/metabolism
3.
J Immunol ; 185(3): 1393-403, 2010 Aug 01.
Article in English | MEDLINE | ID: mdl-20592278

ABSTRACT

X-linked SCID patients are deficient in functional IL-2Rgamma(c) leading to the loss of IL-2/IL-4/IL-7/IL-9/IL-15/IL-21 signaling and a lack of NK and mature T cells. Patients treated with IL-2Rgamma(c) gene therapy have T cells develop; however, their NK cell numbers remain low, suggesting antiviral responses may be compromised. Similarly, IL-2Rgamma(c)(-/-) mice reconstituted with IL-2Rgamma(c) developed few NK cells, and reconstituted T cells exhibited defective proliferative responses suggesting incomplete recovery of IL-2Rgamma(c) signaling. Given the shift toward self-inactivating long terminal repeats with weaker promoters to control the risk of leukemia, we assessed NK and T cell numbers and function in IL-2Rgamma(c)(-/-) mice reconstituted with limiting amounts of IL-2Rgamma(c). Reconstitution resulted in lower IL-2/-15-mediated STAT5 phosphorylation and proliferation in NK and T cells. However, TCR costimulation restored cytokine-driven T cell proliferation to wild-type levels. Vector modifications that improved IL-2Rgamma(c) levels increased cytokine-induced STAT5 phosphorylation in both populations and increased NK cell proliferation demonstrating that IL-2Rgamma(c) levels are limiting. In addition, although the half-lives of both NK and T cells expressing intermediate levels of IL-2Rgamma(c) are reduced compared with wild-type cells, the reduction in NK cell half-live is much more severe than in T cells. Collectively, these data indicate different IL-2Rgamma(c) signaling thresholds for lymphocyte development and proliferation making functional monitoring imperative during gene therapy. Further, our findings suggest that IL-2Rgamma(c) reconstituted T cells may persist more efficiently than NK cells due to compensation for suboptimal IL-2Rgamma(c) signaling by the TCR.


Subject(s)
Cell Differentiation/immunology , Gene Expression Regulation/immunology , Genetic Therapy/methods , Interleukin Receptor Common gamma Subunit/biosynthesis , Interleukin Receptor Common gamma Subunit/genetics , Killer Cells, Natural/immunology , Signal Transduction/immunology , T-Lymphocyte Subsets/immunology , Animals , Cell Differentiation/genetics , Cell Proliferation , Interleukin Receptor Common gamma Subunit/deficiency , Interleukin-15/antagonists & inhibitors , Interleukin-15/physiology , Interleukin-2/antagonists & inhibitors , Interleukin-2/physiology , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, SCID , Phosphorylation/genetics , Phosphorylation/immunology , Receptors, Antigen, T-Cell/deficiency , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/physiology , STAT5 Transcription Factor/antagonists & inhibitors , STAT5 Transcription Factor/metabolism , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/therapy , Signal Transduction/genetics , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/metabolism , Transduction, Genetic
4.
Curr Opin Immunol ; 21(1): 38-46, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19230638

ABSTRACT

Since the discovery of triggering receptor expressed on myeloid cells (TREM)-1 in 2000, evidence documenting the profound ability of the TREM and TREM-like receptors to regulate inflammation has rapidly accumulated. Monocytes, macrophages, myeloid dendritic cells, plasmacytoid dendritic cells, neutrophils, microglia, osteoclasts, and platelets all express at least one member of the TREM family, underscoring the importance of these proteins in the regulation of innate resistance. Recent work on the TREM family includes: characterization of a new receptor expressed on plasmacytoid dendritic cells; definition of a key role for TREM in inflammatory bowel disease and multiple sclerosis; an expanded list of diseases associated with the release of soluble forms of TREM proteins; and identification of the first well characterized TREM ligand: B7-H3, a ligand for TREM-like Transcript (TLT)-2. Moreover, analysis of TREM signaling has now identified key regulatory components and defined pathways that may be responsible for the complex functional interactions between the TREM and toll-like receptors. In addition, there is expanding evidence of a role for TREM in the regulation of integrin function via Plexin-A1. Together these new findings define the TREM and TREM-like receptors as pluripotent modifiers of disease through the integration of inflammatory signals with those associated with leukocyte adhesion.


Subject(s)
Autoimmune Diseases/immunology , Bacterial Infections/immunology , Dendritic Cells/immunology , Membrane Glycoproteins/immunology , Receptors, Immunologic/immunology , Animals , Antigens, CD/immunology , B7 Antigens , Cell Adhesion , Dendritic Cells/metabolism , Feedback, Physiological , Gene Expression Regulation , Humans , Inflammation , Membrane Glycoproteins/metabolism , Osteogenesis , Receptor Cross-Talk , Receptors, Immunologic/metabolism , Signal Transduction , Triggering Receptor Expressed on Myeloid Cells-1
5.
Cell Immunol ; 254(2): 124-34, 2009.
Article in English | MEDLINE | ID: mdl-18828998

ABSTRACT

CD23, the low affinity IgE receptor, is hypothesized to function as a negative regulator of IgE production. Upon discovering reduced CD23 surface levels in 129/SvJ inbred mice, we sought to further investigate 129/SvJ CD23 and to examine its influence on IgE levels. Five amino acid substitutions were found in 129/SvJ CD23. Identical mutations were also observed in CD23 from New Zealand Black and 129P1/ReJ mice. 129/SvJ B cells proliferated more rapidly than those from BALB/c after stimulation with IL-4 and CD40 ligand trimer. However, in vitro IgE levels in supernatants from stimulated 129/SvJ B cells were significantly reduced. Contrary to the in vitro findings, the 129/SvJ CD23 mutations correlated with a hyper IgE phenotype in vivo and 129/SvJ were able to clear Nippostrongylus brasiliensis infection more rapidly than either BALB/c or C57BL/6. Overall, this study further suggests that CD23 is an important regulatory factor for IgE production.


Subject(s)
Immunoglobulin E/immunology , Mutation/genetics , Receptors, IgE/genetics , Receptors, IgE/immunology , Amino Acid Sequence , Animals , Antibody Formation/immunology , Binding Sites , Cell Membrane/immunology , Cells, Cultured , Conserved Sequence , Gene Expression Regulation , Mice , Mice, Inbred Strains , Molecular Sequence Data , RNA, Messenger/genetics , Receptors, IgE/blood , Receptors, IgE/chemistry , Sequence Alignment
6.
Curr Allergy Asthma Rep ; 7(5): 331-7, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17697638

ABSTRACT

Given the importance of immunoglobulin (Ig) E in mediating type I hypersensitivity, inhibiting IgE production would be a general way of controlling allergic disease. The low-affinity IgE receptor (FceRII or CD23) has long been proposed to be a natural regulator of IgE synthesis. In vivo research supporting this concept includes the observation that mice lacking CD23 have increased IgE production whereas mice overexpressing CD23 show strongly suppressed IgE responses. In addition, the finding that mice injected with monoclonal antibody directed against the coiled-coil stalk of CD23 have enhanced soluble CD23 release and increased IgE production demonstrates that full-length, trimeric CD23 is responsible for initiating an IgE inhibitory signal. The recent identification of ADAM10 (a disintegrin and metalloprotease) as the CD23 metalloprotease provides an alternative approach for designing therapies to combat allergic disease. Current data suggest that stabilizing cell-surface CD23 would be a natural means to decrease IgE synthesis and thus control type I hypersensitivity.


Subject(s)
Hypersensitivity/immunology , Immunoglobulin E/metabolism , Receptors, IgE/physiology , Animals , Antibody Formation , Humans , Mice , Mutation , Receptors, IgE/genetics
7.
Nat Immunol ; 7(12): 1293-8, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17072319

ABSTRACT

CD23, the low-affinity immunoglobulin E receptor, is an important modulator of the allergic response and of diseases such as rheumatoid arthritis. The proteolytic release of CD23 from cells is considered a key event in the allergic response. Here we used loss-of-function and gain-of-function experiments with cells lacking or overexpressing candidate CD23-releasing enzymes (ADAM8, ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, ADAM19 and ADAM33), ADAM-knockout mice and a selective inhibitor to identify ADAM10 as the main CD23-releasing enzyme in vivo. Our findings provide a likely target for the treatment of allergic reactions and set the stage for further studies of the involvement of ADAM10 in CD23-dependent pathologies.


Subject(s)
ADAM Proteins/immunology , ADAM Proteins/metabolism , Amyloid Precursor Protein Secretases/immunology , Amyloid Precursor Protein Secretases/metabolism , Membrane Proteins/immunology , Membrane Proteins/metabolism , Receptors, IgE/immunology , Receptors, IgE/metabolism , ADAM10 Protein , Animals , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Electrophoresis, Polyacrylamide Gel , Enzyme-Linked Immunosorbent Assay , Fibroblasts/immunology , Fibroblasts/metabolism , Flow Cytometry , Humans , Immunoblotting , Mice , Mice, Knockout , Transfection
8.
Cell Immunol ; 243(2): 107-17, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17324389

ABSTRACT

To investigate the effects of in vivo CD23 destabilization on CD23 shedding and IgE production, an anti-CD23 stalk monoclonal (19G5), previously shown to enhance proteolysis of CD23 in vitro, was utilized. Compared to isotype control-treated mice, BALB/cJ mice injected with 19G5 displayed significantly enhanced serum soluble CD23 and IgE. Soluble CD23 and IgE levels were also increased in 19G5-treated C57BL/6J mice (intermediate IgE responders); however, the kinetics of the responses differed between the high (BALB/cJ) and intermediate responder mice, suggesting a potential role for CD23 in regulating IgE responder status. The 19G5-induced IgE response was dependent on IL-4 and independent of CD21 as demonstrated through use of IL-4Ralpha and CD21/35-deficient mice, respectively. Overall, the data provide a direct demonstration for CD23's role in regulating IgE production in vivo and suggest that therapies aimed at stabilizing cell surface CD23 would be beneficial in controlling allergic disease.


Subject(s)
Immunoglobulin E/biosynthesis , Nippostrongylus/immunology , Receptors, IgE/blood , Strongylida Infections/immunology , Alum Compounds/chemistry , Animals , Antigens, Helminth/immunology , Cell Membrane/metabolism , Immunization , Immunoglobulin E/blood , Immunoglobulin G/metabolism , Interleukin-4/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , Models, Biological , Receptors, Complement 3d , Signal Transduction , Silver/metabolism
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