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1.
Front Immunol ; 11: 579776, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329550

RESUMO

Mechanisms driving acute graft-versus-host disease (aGVHD) onset in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are still poorly understood. To provide a detailed characterization of tissue-infiltrating T lymphocytes (TL) and search for eventual site-specific specificities, we developed a xenogeneic model of aGVHD in immunodeficient mice. Phenotypic characterization of xenoreactive T lymphocytes (TL) in diseased mice disclosed a massive infiltration of GVHD target organs by an original CD4+CD8+ TL subset. Immunophenotypic and transcriptional profiling shows that CD4+CD8+ TL comprise a major PD1+CD62L-/+ transitional memory subset (>60%) characterized by low level expression of cytotoxicity-related transcripts. CD4+CD8+ TL produce high IL-10 and IL-13 levels, and low IL-2 and IFN-γ, suggestive of regulatory function. In vivo tracking of genetically labeled CD4+ or CD8+ TL subsequently found that CD4+CD8+ TL mainly originate from chronically activated cytotoxic TL (CTL). On the other hand, phenotypic profiling of CD3+ TL from blood, duodenum or rectal mucosa in a cohort of allo-HSCT patients failed to disclose abnormal expansion of CD4+CD8+ TL independent of aGVHD development. Collectively, our results show that acquisition of surface CD4 by xenoreactive CD8+ CTL is associated with functional diversion toward a regulatory phenotype, but rule out a central role of this subset in the pathogenesis of aGVHD in allo-HSCT patients.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Linfócitos T Citotóxicos/imunologia , Animais , Citocinas/metabolismo , Feminino , Humanos , Memória Imunológica , Masculino , Camundongos , Camundongos SCID , Receptor de Morte Celular Programada 1/metabolismo , Transplante Heterólogo
2.
J Exp Med ; 214(7): 2023-2040, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28550161

RESUMO

The CXCL12/CXCR4 signaling exerts a dominant role in promoting hematopoietic stem and progenitor cell (HSPC) retention and quiescence in bone marrow. Gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor have been reported in the WHIM Syndrome (WS), a rare immunodeficiency characterized by lymphopenia. The mechanisms underpinning this remain obscure. Using a mouse model with a naturally occurring WS-linked gain-of-function Cxcr4 mutation, we explored the possibility that the lymphopenia in WS arises from defects at the HSPC level. We reported that Cxcr4 desensitization is required for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors. Alteration in Cxcr4 desensitization resulted in decrease of circulating HSPCs in five patients with WS. This was also evidenced in WS mice and mirrored by accumulation of HSPCs in the spleen, where we observed enhanced extramedullary hematopoiesis. Therefore, efficient Cxcr4 desensitization is critical for lymphoid differentiation of HSPCs, and its impairment is a key mechanism underpinning the lymphopenia observed in mice and likely in WS patients.


Assuntos
Diferenciação Celular/genética , Células-Tronco Hematopoéticas/metabolismo , Linfócitos/metabolismo , Receptores CXCR4/genética , Adulto , Animais , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea/métodos , Sobrevivência Celular/genética , Criança , Citometria de Fluxo , Expressão Gênica , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/metabolismo , Contagem de Linfócitos , Camundongos Transgênicos , Mutação , Doenças da Imunodeficiência Primária , Receptores CXCR4/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Baço/citologia , Baço/metabolismo , Verrugas/genética , Verrugas/metabolismo
3.
Cell Rep ; 17(1): 193-205, 2016 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-27681431

RESUMO

CXCR4 plays a central role in B cell immune response, notably by promoting plasma cell (PC) migration and maintenance in the bone marrow (BM). Gain-of-function mutations in CXCR4 affecting receptor desensitization have been reported in the rare immunodeficiency called WHIM syndrome (WS). Despite lymphopenia, patients mount an immune response but fail to maintain it over time. Using a knockin mouse model phenocopying WS, we showed that, counter-intuitively, a gain of Cxcr4 function inhibited the maintenance of antibody titers after immunization. Although the Cxcr4 mutation intrinsically and locally promoted germinal center response and PC differentiation, antigen-specific PCs were barely detected in the BM, a defect mirrored by early accumulation of immature plasmablasts potentially occupying the survival niches for long-lived PCs. Therefore, fine-tuning of Cxcr4 desensitization is critically required for efficient PC differentiation and maintenance, and absence of such a regulatory process may account for the defective humoral immunity observed in WS patients.


Assuntos
Subpopulações de Linfócitos B/imunologia , Medula Óssea/imunologia , Dessensibilização Imunológica , Síndromes de Imunodeficiência/imunologia , Plasmócitos/imunologia , Receptores CXCR4/imunologia , Verrugas/imunologia , Animais , Anticorpos/sangue , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/patologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Diferenciação Celular , Movimento Celular , Modelos Animais de Doenças , Expressão Gênica , Técnicas de Introdução de Genes , Centro Germinativo , Haptenos , Hemocianinas/administração & dosagem , Humanos , Imunidade Humoral , Imunização , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Camundongos , Camundongos Transgênicos , Ovalbumina/administração & dosagem , Plasmócitos/efeitos dos fármacos , Plasmócitos/patologia , Doenças da Imunodeficiência Primária , Receptores CXCR4/genética , Transdução de Sinais , Verrugas/genética , Verrugas/patologia
4.
Eur J Immunol ; 43(6): 1667-75, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23519784

RESUMO

Patrolling Ly6C(-) monocytes are blood-circulating cells that play a role in inflammation and in the defense against pathogens. Here, we show that similar to natural killer (NK) cells, patrolling monocytes express high levels of S1PR5, a G-coupled receptor for sphingosine-1 phosphate. We found that S1pr5(-/-) mice lack peripheral Ly6C(-) monocytes but have a normal number of these cells in the bone marrow (BM). Various lines of evidence exclude a direct contribution of S1PR5 in the survival of Ly6C(-) monocytes at the periphery. Rather, our data support a role for S1PR5 in the egress of Ly6C(-) monocytes from the BM. In particular, we observed a reduced frequency of patrolling monocytes in BM sinusoids of S1PR5 KO mice. Unexpectedly, S1P was not a chemoattractant for patrolling monocytes and had no significant effect on their viability in vitro. Moreover, the disruption of S1P gradients in vivo did not alter Ly6C(-) monocyte trafficking and viability. These data suggest that S1PR5 regulates the trafficking of monocytes via a mechanism independent of S1P gradients.


Assuntos
Antígenos Ly/metabolismo , Medula Óssea/imunologia , Monócitos/imunologia , Receptores de Lisoesfingolipídeo/metabolismo , Animais , Circulação Sanguínea , Movimento Celular/imunologia , Sobrevivência Celular , Células Cultivadas , Feminino , Homeostase , Vigilância Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Lisoesfingolipídeo/genética
5.
J Transl Med ; 10: 251, 2012 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-23244336

RESUMO

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by B-cell hyper-reactivity and the production of pathogenic anti-nuclear-directed auto-antibodies (Abs). B-cell ontogeny is partly dependent on the CXCL12/CXCR4 axis for which the contribution to SLE pathogenesis remains unclear. CXCR7, the novel receptor for CXCL12, is differentially expressed among memory B-cell subsets. However, its biological role in SLE remains to be explored. METHODS: Relative CXCR4 and CXCR7 expression levels were compared by quantitative PCR in leukocytes from blood samples of 41 Mexican Mestizos patients with SLE and 45 ethnicity-matched healthy subjects. Intracellular and membrane expression of both receptors was analyzed by flow cytometry in naive and Ab-secreting B cells. B-cell responsiveness to CXCL12 was investigated using Transwell-based chemotaxis assays. Data were analyzed using the Kruskal-Wallis test for comparisons of values amongst healthy controls and patients with inactive or active SLE, and non-parametrically using the Mann-Whitney U-test for multiple comparisons and unpaired samples. Correlations were determined by Spearman's ranking. RESULT: SLE leukocytes displayed reduced levels of CXCR4 and CXCR7 transcripts. In SLE patients, a significant defect in CXCR4 expression was detected at the surface of naive and Ab-secreting B cells, associated with an abnormal intracellular localization of the receptor. CXCR7 predominantly localized in cytosolic compartments of B cells from healthy and SLE individuals. Disease activity did not impact on these expression patterns. Altered receptor compartmentalization correlated with an impaired CXCL12-promoted migration of SLE B cells. CONCLUSIONS: Our data highlight a down-regulation of CXCL12 receptors on circulating B cells from SLE patients that likely influences their migratory behavior and distribution.


Assuntos
Linfócitos B/metabolismo , Etnicidade , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Receptores CXCR4/metabolismo , Receptores CXCR/metabolismo , Adulto , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Contagem de Células , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Quimiocina CXCL12/farmacologia , Quimiotaxia/efeitos dos fármacos , Demografia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Masculino , México , Pessoa de Meia-Idade , Plasmócitos/efeitos dos fármacos , Plasmócitos/metabolismo , Plasmócitos/patologia , Receptores CXCR/genética , Receptores CXCR4/genética , Adulto Jovem
6.
Blood ; 119(24): 5722-30, 2012 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-22438253

RESUMO

Desensitization controls G protein-dependent signaling of chemokine receptors. We investigate the physiologic implication of this process for CXCR4 in a mouse model harboring a heterozygous mutation of the Cxcr4 gene, which engenders a desensitization-resistant receptor. Such anomaly is linked to the warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, a human rare combined immunodeficiency. Cxcr4(+/mutant(1013)) mice display leukocytes with enhanced responses to Cxcl12 and exhibit leukopenia as reported in patients. Treatment with CXCL12/CXCR4 antagonists transiently reverses blood anomalies, further demonstrating the causal role of the mutant receptor in the leukopenia. Strikingly, neutropenia occurs in a context of normal bone marrow architecture and granulocyte lineage maturation, indicating a minor role for Cxcr4-dependent signaling in those processes. In contrast, Cxcr4(+/1013) mice show defective thymopoiesis and B-cell development, accounting for circulating lymphopenia. Concomitantly, mature T and B cells are abnormally compartmentalized in the periphery, with a reduction of primary follicles in the spleen and their absence in lymph nodes mirrored by an unfurling of the T-cell zone. These mice provide a model to decipher the role of CXCR4 desensitization in the homeostasis of B and T cells and to investigate which manifestations of patients with WHIM syndrome may be overcome by dampening the gain of CXCR4 function.


Assuntos
Compartimento Celular/imunologia , Dessensibilização Imunológica , Linfócitos/imunologia , Receptores CXCR4/imunologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Benzilaminas , Medula Óssea/patologia , Quimiocina CXCL12/farmacologia , Quimiotaxia/efeitos dos fármacos , Doença Crônica , Ciclamos , Compostos Heterocíclicos/farmacologia , Homeostase/efeitos dos fármacos , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Contagem de Linfócitos , Linfócitos/efeitos dos fármacos , Camundongos , Mutação/genética , Neutropenia/sangue , Neutropenia/patologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia
7.
Blood ; 118(18): 4863-71, 2011 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-21911833

RESUMO

During development, natural killer (NK) cells exit the BM to reach the blood. CXCR4 retains NK cells in the BM, whereas the sphingosine-1 phosphate receptor 5 (S1P5) promotes their exit from this organ. However, how the action of these receptors is coordinated to preserve NK-cell development in the BM parenchyma while providing mature NK cells at the periphery is unclear. The role of CXCR4 and S1P5 in NK-cell recirculation at the periphery is also unknown. In the present study, we show that, during NK-cell differentiation, CXCR4 expression decreases whereas S1P5 expression increases, thus favoring the exit of mature NK cells via BM sinusoids. Using S1P5(-/-) mice and a new knockin mouse model in which CXCR4 cannot be desensitized (a mouse model of warts, hypogammaglobulinemia, infections, and myelokathexis [WHIM] syndrome), we demonstrate that NK-cell exit from the BM requires both CXCR4 desensitization and S1P5 engagement. These 2 signals occur independently of each other: CXCR4 desensitization is not induced by S1P5 engagement and vice versa. Once in the blood, the S1P concentration increases and S1P5 responsiveness decreases. This responsiveness is recovered in the lymph nodes to allow NK-cell exit via lymphatics in a CXCR4-independent manner. Therefore, coordinated changes in CXCR4 and S1P5 responsiveness govern NK-cell trafficking.


Assuntos
Movimento Celular , Dessensibilização Imunológica , Células Matadoras Naturais/fisiologia , Receptores CXCR4/imunologia , Receptores de Lisoesfingolipídeo/imunologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/fisiologia , Movimento Celular/genética , Movimento Celular/imunologia , Movimento Celular/fisiologia , Dessensibilização Imunológica/métodos , Técnicas de Introdução de Genes , Esquemas de Imunização , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfonodos/citologia , Linfonodos/imunologia , Linfonodos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CXCR4/genética , Receptores CXCR4/fisiologia , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/fisiologia
8.
Med Sci (Paris) ; 27(4): 391-7, 2011 Apr.
Artigo em Francês | MEDLINE | ID: mdl-21524404

RESUMO

Currently, more than 200 primary immunodeficiency diseases have been discovered. In most cases, genetic defects affect the expression or the function of proteins involved in immune development and homeostasis. Some orphan immuno-hematological disorders are characterized by an abnormal leukocyte trafficking, a notion predictive of an anomaly of the chemokine/chemokine receptor system. In this review, we focus on recent advances in the characterization of dysfunctions of the CXCL12 (SDF-1)/CXCR4 signaling axis in two rare human immunodeficiencies, one associated with a loss of CXCR4 function, the Idiopathic CD4(+) T-cell Lymphocytopenia, and the other with a gain of CXCR4 function, the WHIM syndrome.


Assuntos
Síndromes de Imunodeficiência/terapia , Receptores CXCR4/fisiologia , Arrestinas/fisiologia , Linfócitos T CD4-Positivos/imunologia , Quimiocina CXCL12/fisiologia , Quimiotaxia/fisiologia , Desenho de Fármacos , Quinase 3 de Receptor Acoplado a Proteína G/fisiologia , Homeostase/fisiologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/fisiopatologia , Linfopenia/genética , Linfopenia/imunologia , Modelos Biológicos , Doenças da Imunodeficiência Primária , Receptores CXCR4/deficiência , Receptores CXCR4/genética , Receptores Acoplados a Proteínas G/fisiologia , Transdução de Sinais/fisiologia , Verrugas/genética , Verrugas/imunologia , Verrugas/fisiopatologia , beta-Arrestinas
9.
Biol Aujourdhui ; 204(4): 273-84, 2010.
Artigo em Francês | MEDLINE | ID: mdl-21215244

RESUMO

Chemokines are small cytokine-like secreted proteins that govern migration of leukocytes to their specific niches in lymphoid organs and to inflammatory sites. They mediate their functions by binding to and activating chemokine receptors, which belong to the heptahelical G protein-coupled receptor family. The CXC chemokine Stromal cell Derived Factor-1 (SDF-1/CXCL12) is the sole natural ligand for the broadly expressed CXCR4 receptor and acts as a chemoattractant for many leukocyte subsets. The CXCL12/CXCR4 axis exerts critical activities in homeostatic processes such as organogenesis, hematopoiesis and leukocyte trafficking. Dysregulations of CXCR4 signaling and/or expression are associated with several infectious, inflammatory, autoimmune and malignant conditions. In light of recent data, we review here CXCR4 dysfunctions unveiled in two rare human immunodeficiency disorders, one characterized by a gain of CXCR4 function, the WHIM syndrome, and the other by a loss of CXCR4 function, the idiopathic CD4(+) T-cell lymphocytopenia.


Assuntos
Quimiocina CXCL12/fisiologia , Receptores CXCR4/fisiologia , T-Linfocitopenia Idiopática CD4-Positiva/imunologia , T-Linfocitopenia Idiopática CD4-Positiva/fisiopatologia , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/fisiopatologia , Doenças da Imunodeficiência Primária , Transdução de Sinais , Verrugas/imunologia , Verrugas/fisiopatologia
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