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1.
Front Immunol ; 10: 1159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231367

RESUMO

Persistent T cell antigen receptor (TCR) signaling by CD8 T cells is a feature of cancer and chronic infections and results in the sustained expression of, and signaling by, inhibitory receptors, which ultimately impair cytotoxic activity via poorly characterized mechanisms. We have previously determined that the LPA5 GPCR expressed by CD8 T cells, upon engaging the lysophosphatidic acid (LPA) bioactive serum lipid, functions as an inhibitory receptor able to negatively regulate TCR signaling. Notably, the levels of LPA and autotaxin (ATX), the phospholipase D enzyme that produces LPA, are often increased in chronic inflammatory disorders such as chronic infections, autoimmune diseases, obesity, and cancer. In this report, we demonstrate that LPA engagement selectively by LPA5 on human and mouse CD8 T cells leads to the inhibition of several early TCR signaling events including intracellular calcium mobilization and ERK activation. We further show that, as a consequence of LPA5 suppression of TCR signaling, the exocytosis of perforin-containing granules is significantly impaired and reflected by repressed in vitro and in vivo CD8 T cell cytolytic activity. Thus, these data not only document LPA5 as a novel inhibitory receptor but also determine the molecular and biochemical mechanisms by which a naturally occurring serum lipid that is elevated under settings of chronic inflammation signals to suppress CD8 T cell killing activity in both human and murine cells. As diverse tumors have repeatedly been shown to aberrantly produce LPA that acts in an autocrine manner to promote tumorigenesis, our findings further implicate LPA in activating a novel inhibitory receptor whose signaling may be therapeutically silenced to promote CD8 T cell immunity.

2.
J Clin Invest ; 129(3): 965-968, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30714991

RESUMO

Primary antibody deficiencies are the most common immunodeficiencies in humans; however, identification of the underlying genetic and biochemical basis for these diseases is often difficult, given that these deficiencies typically involve complex genetic etiologies. In this issue of the JCI, Bouafia et al. performed whole-exome sequencing on a pair of siblings with primary antibody deficiencies and identified genetic mutations that result in a deficiency of ARHGEF1, a hematopoietic intracellular signaling molecule that transmits signals from GPCRs. ARHGEF1-deficient lymphocytes from the affected siblings exhibited important functional deficits that indicate that loss of ARHGEF1 accounts for the observed primary antibody deficiency, which manifests in an inability to mount antibody responses to vaccines and pathogens. Thus, this report demonstrates an important role for ARHGEF1 in GPCR signal transduction required for appropriate adaptive immune responses in humans.


Assuntos
Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP , Humanos , Linfócitos , Fatores de Troca de Nucleotídeo Guanina Rho , Transdução de Sinais
3.
PLoS One ; 14(2): e0211446, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30735510

RESUMO

It is common practice for researchers to use antibodies to remove a specific cell type to infer its function. However, it is difficult to completely eliminate a cell type and there is often limited or no information as to how the cells which survive depletion are affected. This is particularly important for CD8+ T cells for two reasons. First, they are more resistant to mAb-mediated depletion than other lymphocytes. Second, targeting either the CD8α or CD8ß chain could induce differential effects. We show here that two commonly used mAbs, against either the CD8α or CD8ß subunit, can differentially affect cellular metabolism. Further, in vivo treatment leaves behind a population of CD8+ T cells with different phenotypic and functional attributes relative to each other or control CD8+ T cells. The impact of anti-CD8 antibodies on CD8+ T cell phenotype and function indicates the need to carefully consider the use of these, and possibly other "depleting" antibodies, as they could significantly complicate the interpretation of results or change the outcome of an experiment. These observations could impact how immunotherapy and modulation of CD8+ T cell activation is pursued.


Assuntos
Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/imunologia , Depleção Linfocítica/métodos , Transferência Adotiva , Animais , Anticorpos Monoclonais , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/classificação , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Citotoxicidade Imunológica , Feminino , Memória Imunológica , Imunofenotipagem , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
5.
Blood ; 127(2): 216-20, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26468226

RESUMO

Mutations of the Wiskott-Aldrich syndrome gene (WAS) are responsible for Wiskott-Aldrich syndrome (WAS), a disease characterized by thrombocytopenia, eczema, immunodeficiency, and autoimmunity. Mice with conditional deficiency of Was in B lymphocytes (B/WcKO) have revealed a critical role for WAS protein (WASP) expression in B lymphocytes in the maintenance of immune homeostasis. Neural WASP (N-WASP) is a broadly expressed homolog of WASP, and regulates B-cell signaling by modulating B-cell receptor (BCR) clustering and internalization. We have generated a double conditional mouse lacking both WASP and N-WASP selectively in B lymphocytes (B/DcKO). Compared with B/WcKO mice, B/DcKO mice showed defective B-lymphocyte proliferation and impaired antibody responses to T-cell-dependent antigens, associated with decreased autoantibody production and lack of autoimmune kidney disease. These results demonstrate that N-WASP expression in B lymphocytes is required for the development of autoimmunity of WAS and may represent a novel therapeutic target in WAS.


Assuntos
Autoimunidade/genética , Linfócitos B/imunologia , Proteína Neuronal da Síndrome de Wiskott-Aldrich/fisiologia , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/imunologia , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Deleção de Genes , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/imunologia , Síndrome de Wiskott-Aldrich/patologia , Proteína Neuronal da Síndrome de Wiskott-Aldrich/genética
6.
J Clin Invest ; 125(11): 4135-48, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26457731

RESUMO

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Citocinas/imunologia , Proteínas de Ligação a DNA/deficiência , Doença Granulomatosa Crônica/imunologia , Proteínas de Homeodomínio/imunologia , Proteínas Nucleares/deficiência , Imunodeficiência Combinada Severa/imunologia , Adolescente , Adulto , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Especificidade de Anticorpos , Autoanticorpos/sangue , Doenças Autoimunes/genética , Criança , Pré-Escolar , RNA Helicases DEAD-box/imunologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/terapia , Proteínas de Homeodomínio/genética , Humanos , Lactente , Helicase IFIH1 Induzida por Interferon , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas Nucleares/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Receptores Toll-Like/agonistas , Receptores Toll-Like/imunologia , Viroses/imunologia , Adulto Jovem
7.
Stem Cells ; 33(4): 1345-58, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25546133

RESUMO

Ionizing radiation (IR) is associated with reduced hematopoietic function and increased risk of hematopoietic malignancies, although the mechanisms behind these relationships remain poorly understood. Both effects of IR have been commonly attributed to the direct induction of DNA mutations, but evidence supporting these hypotheses is largely lacking. Here we demonstrate that IR causes long-term, somatically heritable, cell-intrinsic reductions in hematopoietic stem cell (HSC) and multipotent hematopoietic progenitor cell (mHPC) self-renewal that are mediated by C/EBPα and reversed by Notch. mHPC from previously irradiated (>9 weeks prior), homeostatically restored mice exhibit gene expression profiles consistent with their precocious differentiation phenotype, including decreased expression of HSC-specific genes and increased expression of myeloid program genes (including C/EBPα). These gene expression changes are reversed by ligand-mediated activation of Notch. Loss of C/EBPα expression is selected for within previously irradiated HSC and mHPC pools and is associated with reversal of IR-dependent precocious differentiation and restoration of self-renewal. Remarkably, restoration of mHPC self-renewal by ligand-mediated activation of Notch prevents selection for C/EBPα loss of function in previously irradiated mHPC pools. We propose that environmental insults prompt HSC to initiate a program limiting their self-renewal, leading to loss of the damaged HSC from the pool while allowing this HSC to temporarily contribute to differentiated cell pools. This "programmed mediocrity" is advantageous for the sporadic genotoxic insults animals have evolved to deal with but becomes tumor promoting when the entire HSC compartment is damaged, such as during total body irradiation, by increasing selective pressure for adaptive oncogenic mutations.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/efeitos da radiação , Células-Tronco Hematopoéticas/efeitos da radiação , Células-Tronco Multipotentes/efeitos da radiação , Radiação Ionizante , Receptores Notch/efeitos da radiação , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/fisiologia , Diferenciação Celular/fisiologia , Diferenciação Celular/efeitos da radiação , Proliferação de Células/fisiologia , Proliferação de Células/efeitos da radiação , Células Cultivadas , Células-Tronco Hematopoéticas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Multipotentes/fisiologia , Receptores Notch/fisiologia
9.
Clin Immunol ; 146(2): 84-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23280491

RESUMO

X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency syndrome associated with the inability to control Epstein-Barr virus (EBV), lymphoma, and hypogammaglobulinemia. XLP is caused by mutations in the SH2D1A gene, which encodes the SLAM-associated protein (SAP), or in the BIRC4 gene, which encodes the X-linked inhibitor of apoptosis protein (XIAP). Here we report a patient with recurrent respiratory tract infections and early onset agammaglobulinemia who carried a unique disease-causing intronic loss-of-function mutation in SH2D1A. The intronic mutation affected SH2D1A gene transcription but not mRNA splicing, and led to markedly reduced level of SAP protein. Despite undetectable serum immunoglobulins, the patient's B cells replicated and differentiated into antibody producing cells normally in vitro.


Assuntos
Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Íntrons/genética , Agamaglobulinemia/tratamento farmacológico , Animais , Pré-Escolar , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Íntrons/imunologia , Masculino , Camundongos , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Domínios de Homologia de src/genética , Domínios de Homologia de src/imunologia
10.
Blood ; 119(12): 2819-28, 2012 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-22302739

RESUMO

Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS gene that encodes for a protein (WASp) involved in cytoskeleton organization in hematopoietic cells. Several distinctive abnormalities of T, B, and natural killer lymphocytes; dendritic cells; and phagocytes have been found in WASp-deficient patients and mice; however, the in vivo consequence of WASp deficiency within individual blood cell lineages has not been definitively evaluated. By conditional gene deletion we have generated mice with selective deficiency of WASp in the B-cell lineage (B/WcKO mice). We show that this is sufficient to cause a severe reduction of marginal zone B cells and inability to respond to type II T-independent Ags, thereby recapitulating phenotypic features of complete WASp deficiency. In addition, B/WcKO mice showed prominent signs of B-cell dysregulation, as indicated by an increase in serum IgM levels, expansion of germinal center B cells and plasma cells, and elevated autoantibody production. These findings are accompanied by hyperproliferation of WASp-deficient follicular and germinal center B cells in heterozygous B/WcKO mice in vivo and excessive differentiation of WASp-deficient B cells into class-switched plasmablasts in vitro, suggesting that WASp-dependent B cell-intrinsic mechanisms critically contribute to WAS-associated autoimmunity.


Assuntos
Linfócitos B/citologia , Linfócitos B/imunologia , Proteína da Síndrome de Wiskott-Aldrich/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/imunologia , Contagem de Células , Modelos Animais de Doenças , Citometria de Fluxo , Imunofluorescência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína da Síndrome de Wiskott-Aldrich/deficiência , Proteína da Síndrome de Wiskott-Aldrich/genética
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