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1.
J Allergy Clin Immunol ; 143(2): 712-725.e5, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29800647

RESUMO

BACKGROUND: Autosomal dominant gain-of-function mutations in human stimulator of interferon genes (STING) lead to a severe autoinflammatory disease called STING-associated vasculopathy with onset in infancy that is associated with enhanced expression of interferon-stimulated gene transcripts. OBJECTIVE: The goal of this study was to analyze the phenotype of a new mouse model of STING hyperactivation and the role of type I interferons in this system. METHODS: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse STING, corresponding to a recurrent mutation seen in human patients with STING-associated vasculopathy with onset in infancy. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. STING V154M/wild-type (WT) mice were crossed to IFN-α/ß receptor (IFNAR) knockout mice to evaluate the type I interferon dependence of the mutant Sting phenotype recorded. RESULTS: In STING V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T, and natural killer cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B- and T-cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Although the V154M/WT mutant demonstrated increased expression of interferon-stimulated genes, the SCID phenotype was not reversed in STING V154M/WT IFNAR knockout mice. However, the antiproliferative defect in T cells was rescued partially by IFNAR deficiency. CONCLUSIONS: STING gain-of-function mice developed an interferon-independent SCID phenotype with a T-cell, B-cell, and natural killer cell developmental defect and hypogammaglobulinemia that is associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was partially interferon dependent.


Assuntos
Linfócitos B/fisiologia , Inflamação/genética , Células Matadoras Naturais/imunologia , Proteínas de Membrana/genética , Mutação/genética , Imunodeficiência Combinada Severa/genética , Linfócitos T/fisiologia , Agamaglobulinemia , Animais , Diferenciação Celular/genética , Modelos Animais de Doenças , Humanos , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Interferon alfa e beta/genética
2.
J Clin Invest ; 132(2)2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34813502

RESUMO

Although negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naive B cell positive selection remains elusive. Using 2 humanized mouse models, we demonstrate that there was strong skewing of the expressed immunoglobulin repertoire upon transit into the peripheral naive B cell pool. This positive selection of expanded naive B cells in humanized mice resembled that observed in healthy human donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymus-derived Tregs and MHC class II-restricted self-antigen presentation by B cells. Indeed, both defective MHC class II expression on B cells of patients with rare bare lymphocyte syndrome and prevention of self-antigen presentation via HLA-DM inhibition in humanized mice resulted in the production of autoreactive naive B cells. These latter observations suggest that Tregs repressed autoreactive naive B cells continuously produced by the bone marrow. Thus, a model emerged, in which both positive and negative selection shaped the human naive B cell repertoire and that each process was mediated by fundamentally different molecular and cellular mechanisms.


Assuntos
Apresentação de Antígeno , Linfócitos B/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Imunodeficiência Combinada Severa/imunologia , Linfócitos T Reguladores/imunologia , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
3.
Autophagy ; 15(2): 280-294, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30196744

RESUMO

The involvement of macroautophagy/autophagy proteins in B-cell receptor (BCR) trafficking, although suspected, is not well understood. We show that ATG5 (autophagy related 5) contributes to BCR polarization after stimulation and internalization into LAMP1 (lysosomal-associated membrane protein 1)+ and major histocompatibility complex class II (MHC-II)+ compartments. BCR polarization is crucial in the context of immobilized antigen processing. Moreover, antigen presentation to cognate T cells is decreased in the absence of ATG5 when the model antigen OVAL/ovalbumin is provided in an immobilized form in contrast to the normal presentation of soluble OVAL. We further show that ATG5 is required for centrosome polarization and actin nucleation in the immune synapse area. This event is accompanied by an increased interaction between ATG16L1 (autophagy related 16-like 1 [S. cerevisiae]) and the microtubule-organizing center-associated protein PCM1 (pericentriolar material 1). In the human B cell line BJAB, PCM1 is required for BCR polarization after stimulation. We thus propose that the ATG12 (autophagy related 12)-ATG5-ATG16L1 complex under BCR stimulation allows its interaction with PCM1 and consequently facilitates centrosome relocalization to the immune synapse, optimizing the presentation of particulate antigens. Abbreviations: ACTB: actin beta; ACTR2/3: ARP2/3 actin-related protein 2/3; APC: antigen-presenting cells; ATG: autophagy-related; BCR: B cell receptor; BECN1/Beclin 1: beclin 1, autophagy related; CDC42: cell division cycle 42; Cr2: complement receptor 2; CSFE: carboxyfluorescein succinimidyl ester; DAPI: 4',6-diamidino-2-phenylindole dihydrochloride; EEA1: early endosome antigen 1; ELISA: enzyme-linked immunosorbent assay; FITC: fluorescein isothyocyanate; GC: germinal center; GJA1/CX3: gap junction protein, alpha 1; Ig: immunoglobulin; LAMP1: lysosomal-associated membrane protein 1; LAP: LC3-associated phagocytosis; LM: littermate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen activated protein kinase; MHC-II: major histocompatibility complex class II; MIIC: MHC class II compartment; OVAL: ovalbumin; PBS: phosphate-buffered saline; PCM1: pericentriolar material 1; PtdIns3K: phosphatidylinositol 3-kinase; PTPRC/CD45RB/B220; Protein tyrosine phosphatase, receptor type, C; SYK: spleen tyrosine kinase; TBS: Tris-buffered saline; TCR: T cell receptor; ULK1: unc-51 like kinase 1.


Assuntos
Apresentação de Antígeno , Proteína 5 Relacionada à Autofagia/metabolismo , Linfócitos B/citologia , Linfócitos B/metabolismo , Polaridade Celular , Material Particulado/metabolismo , Animais , Autoantígenos/metabolismo , Autofagia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Citoesqueleto/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Sinapses Imunológicas/metabolismo , Lisossomos/metabolismo , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Transporte Proteico , Receptores de Antígenos de Linfócitos B/metabolismo , Vesículas Transportadoras/metabolismo
4.
Front Immunol ; 9: 2627, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30515153

RESUMO

[This corrects the article DOI: 10.3389/fimmu.2018.01801.].

5.
Front Immunol ; 9: 1801, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30127786

RESUMO

Autophagy is a catabolic mechanism, allowing the degradation of cytoplasmic content via lysosomal activity. Several forms of autophagy are described in mammals. Macroautophagy leads to integration of cytoplasmic portions into vesicles named autophagosomes that ultimately fuse with lysosomes. Chaperone-mediated autophagy is in contrast the direct translocation of protein in lysosomes. Macroautophagy is central to lymphocyte homeostasis. Although its role is controversial in lymphocyte development and in naive cell survival, it seems particularly involved in the maintenance of certain lymphocyte subtypes. Its importance in memory B and T cells biology has recently emerged. Moreover, some effector cells like plasma cells rely on autophagy for survival. Autophagy is central to glucose and lipid metabolism, and to the maintenance of organelles like mitochondria and endoplasmic reticulum. In addition macroautophagy, or individual components of its machinery, are also actors in antigen presentation by B cells, a crucial step to receive help from T cells, this crosstalk favoring their final differentiation into memory or plasma cells. Autophagy is deregulated in several autoimmune or autoinflammatory diseases like systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and Crohn's disease. Some treatments used in these pathologies impact autophagic activity, even if the causal link between autophagy regulation and the efficiency of the treatments has not yet been clearly established. In this review, we will first discuss the mechanisms linking autophagy to lymphocyte subtype survival and the signaling pathways involved. Finally, potential impacts of autophagy modulation in lymphocytes on the course of these diseases will be approached.


Assuntos
Autofagia , Homeostase , Inflamação/imunologia , Ativação Linfocitária , Subpopulações de Linfócitos/imunologia , Animais , Humanos , Transdução de Sinais
6.
Sci Rep ; 8(1): 5951, 2018 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-29654322

RESUMO

Studies of mice deficient for autophagy in T cells since thymic development, concluded that autophagy is integral to mature T cell homeostasis. Basal survival and functional impairments in vivo, limited the use of these models to delineate the role of autophagy during the immune response. We generated Atg5 f/f distal Lck (dLck)-cre mice, with deletion of autophagy only at a mature stage. In this model, autophagy deficiency impacts CD8+ T cell survival but has no influence on CD4+ T cell number and short-term activation. Moreover, autophagy in T cells is dispensable during early humoral response but critical for long-term antibody production. Autophagy in CD4+ T cells is required to transfer humoral memory as shown by injection of antigen-experienced cells in naive mice. We also observed a selection of autophagy-competent cells in the CD4+ T cell memory compartment. We performed in vitro differentiation of memory CD4+ T cells, to better characterize autophagy-deficient memory cells. We identified mitochondrial and lipid load defects in differentiated memory CD4+ T cells, together with a compromised survival, without any collapse of energy production. We then propose that memory CD4+ T cells rely on autophagy for their survival to regulate toxic effects of mitochondrial activity and lipid overload.


Assuntos
Autofagia/imunologia , Linfócitos T CD4-Positivos/imunologia , Memória Imunológica/imunologia , Animais , Anticorpos/imunologia , Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Sobrevivência Celular/imunologia , Homeostase/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/imunologia , Mitocôndrias/imunologia
7.
Med Sci (Paris) ; 32(3): 281-9, 2016 Mar.
Artigo em Francês | MEDLINE | ID: mdl-27011247

RESUMO

Macroautophagy often abbreviated by "autophagy" is an intracellular degradation mechanism linked to lysosomal activity. Autophagy is conserved from yeast to mammals and plays a role in the response to energetic stress and in organelle homeostasis. Autophagy is also involved in the regulation of immunity, in particular in the adaptive immune response, which involves B and T lymphocytes. It was indeed shown that autophagy impacts the development of B and T cells as well as the education of T cells in the thymus. Autophagy also modulates activation, survival and polarization of T cells. It plays a role in antigen presentation by B cells, and in their TLR-mediated activation, and thus likely in their initial activation. Finally, autophagy is required for the survival of memory lymphocytes and effector cells like antibody-producing plasma cells. Interestingly, autophagy is deregulated in several autoimmune pathologies. The modulation of this phenomenon could possibly lead to new treatments aiming at limiting lymphocyte activation driving these pathologies.


Assuntos
Autofagia/fisiologia , Linfócitos B/fisiologia , Homeostase/imunologia , Linfócitos T/fisiologia , Animais , Humanos , Imunidade Inata/fisiologia
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