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1.
Nat Immunol ; 24(12): 2108-2120, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37932457

RESUMEN

Regulatory T cells (Treg cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal Treg cells to regulate helper T17 cell (TH17 cell) immunity. Selectively increased intestinal TH17 cell responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+CD62Llo Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a new Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.


Asunto(s)
Interleucina-27 , Linfocitos T Reguladores , Ratones , Animales , Linfocitos T Colaboradores-Inductores , Tolerancia Inmunológica , Inmunidad Celular , Células Th17
2.
Cell ; 142(6): 914-29, 2010 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-20850013

RESUMEN

Foxp3(+) regulatory T (Treg) cells maintain immune homeostasis by limiting different types of inflammatory responses. Here, we report that miR-146a, one of the miRNAs prevalently expressed in Treg cells, is critical for their suppressor function. The deficiency of miR-146a in Treg cells resulted in a breakdown of immunological tolerance manifested in fatal IFNγ-dependent immune-mediated lesions in a variety of organs. This was likely due to augmented expression and activation of signal transducer and activator transcription 1 (Stat1), a direct target of miR-146a. Likewise, heightened Stat1 activation in Treg cells subjected to a selective ablation of SOCS1, a key negative regulator of Stat1 phosphorylation downstream of the IFNγ receptor, was associated with analogous Th1-mediated pathology. Our results suggest that specific aspects of Treg suppressor function are controlled by a single miRNA and that an optimal range of Stat1 activation is important for Treg-mediated control of Th1 responses and associated autoimmunity.


Asunto(s)
MicroARNs/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Interferón gamma/inmunología , Ratones , Ratones Noqueados , MicroARNs/genética , Factor de Transcripción STAT1/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología
3.
Immunity ; 43(1): 52-64, 2015 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-26163372

RESUMEN

MicroRNA (miRNA)-dependent regulation of gene expression confers robustness to cellular phenotypes and controls responses to extracellular stimuli. Although a single miRNA can regulate expression of hundreds of target genes, it is unclear whether any of its distinct biological functions can be due to the regulation of a single target. To explore in vivo the function of a single miRNA-mRNA interaction, we mutated the 3' UTR of a major miR-155 target (SOCS1) to specifically disrupt its regulation by miR-155. We found that under physiologic conditions and during autoimmune inflammation or viral infection, some immunological functions of miR-155 were fully or largely attributable to the regulation of SOCS1, whereas others could be accounted only partially or not at all by this interaction. Our data suggest that the role of a single miRNA-mRNA interaction is dependent on cell type and biological context.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Células Asesinas Naturales/inmunología , MicroARNs/genética , Proteínas Supresoras de la Señalización de Citocinas/genética , Linfocitos T Reguladores/inmunología , Regiones no Traducidas 3'/genética , Animales , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Perfilación de la Expresión Génica , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Células Asesinas Naturales/trasplante , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Muromegalovirus/inmunología , Mutación , ARN Mensajero/genética , Proteína 1 Supresora de la Señalización de Citocinas
4.
J Immunol ; 198(10): 3919-3926, 2017 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-28404635

RESUMEN

miR-23∼27∼24 was recently implicated in restricting Th2 immunity, as well as the differentiation and function of other effector T cell lineages. Interestingly, miR-24, unlike other family members, actually promotes Th1 and Th17 responses. In this article, we show that miR-24 drives the production of IFN-γ and IL-17 in T cells at least in part through targeting TCF1, a transcription factor known for its role in limiting Th1 and Th17 immunity. Surprisingly, whereas TCF1 was previously shown to promote Th2 responses through inducing GATA3, enforced TCF1 expression in miR-24-overexpressing T cells led to further downregulation of IL-4 and GATA3 expression, suggesting miR-24-mediated inhibition of Th2 immunity cannot be attributed to TCF1 repression by miR-24. Together, our data demonstrate a novel miR-24-TCF1 pathway in controlling effector cytokine production by T cells and further suggest miR-24 could function as a key upstream molecule regulating TCF1-mediated immune responses.


Asunto(s)
Factor Nuclear 1-alfa del Hepatocito/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Subgrupos de Linfocitos T/inmunología , Animales , Diferenciación Celular , Citocinas/biosíntesis , Citocinas/inmunología , Regulación hacia Abajo , Factor de Transcripción GATA3/biosíntesis , Factor Nuclear 1-alfa del Hepatocito/genética , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-17/biosíntesis , Interleucina-17/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Activación de Linfocitos , Ratones , Transducción de Señal , Subgrupos de Linfocitos T/metabolismo , Células TH1/inmunología , Células Th17/inmunología , Células Th2/inmunología
5.
PLoS Pathog ; 11(2): e1004635, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25658840

RESUMEN

IFNγ signaling drives dendritic cells (DCs) to promote type I T cell (Th1) immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg) cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population.


Asunto(s)
Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Interferón gamma/inmunología , Linfocitos T Reguladores/inmunología , Toxoplasmosis/inmunología , Animales , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inflamación/inmunología , Ratones , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/inmunología , Proteínas de Dominio T Box/inmunología , Linfocitos T Reguladores/citología , Células TH1/citología , Células TH1/inmunología
6.
J Exp Med ; 220(10)2023 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-37516921

RESUMEN

Effector regulatory T cells (eTregs) exhibit distinct homeostatic properties and superior suppressor capacities pivotal for controlling immune responses mediated by their conventional T cell counterpart. While the role of microRNAs (miRNAs) in Tregs has been well-established, how miRNAs regulate eTregs remains poorly understood. Here, we demonstrate that miR-15/16 clusters act as key regulators in limiting eTreg responses. Loss of miR-15/16 clusters leads to increased eTreg frequencies with enhanced suppressor function. Consequently, mice with Treg-specific ablation of miR-15/16 clusters display attenuated immune responses during neuroinflammation and upon both infectious and non-infectious challenges. Mechanistically, miR-15/16 clusters exert their regulatory effect in part through repressing IRF4, a transcription factor essential for eTreg differentiation and function. Moreover, miR-15/16 clusters also directly target neuritin, an IRF4-dependent molecule, known for its role in Treg-mediated regulation of plasma cell responses. Together, we identify an miRNA family that controls an important Treg subset and further demonstrate that eTreg responses are tightly regulated at both transcriptional and posttranscriptional levels.


Asunto(s)
MicroARNs , Linfocitos T Reguladores , Animales , Ratones , Activación de Linfocitos , Diferenciación Celular/genética , Homeostasis , MicroARNs/genética
7.
bioRxiv ; 2023 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-36865314

RESUMEN

Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+TCF1+ Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

8.
J Exp Med ; 218(11)2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34554189

RESUMEN

IL-27 controls a diverse range of immune responses in many disease settings. Here, we identify intestinal epithelial cells (IECs) as one of the major IL-27 cellular sources in the gut-associated tissue. Unlike IL-27 secreted by innate immune cells, gut epithelial IL-27 is dispensable for T-bet+ regulatory T cell (T reg cell) differentiation or IL-10 induction. Rather, IEC-derived IL-27 specifically promotes a distinct CD8αα+CD4+ intraepithelial lymphocyte (IEL) population that acquires their functional differentiation at the intestinal epithelium. Loss of IL-27 in IECs leads to a selective defect in CD8αα+CD4+ IELs over time. Consequently, mice with IEC-specific IL-27 ablation exhibited elevated pathogen burden during parasitic infection, and this could be rescued by transfer of exogenous CD8αα+CD4+ IELs. Collectively, our data reveal that in addition to its known regulatory properties in preventing immune hyperactivity, gut epithelial IL-27 confers barrier immunity by inducing a specific IEL subset and further suggest that IL-27 produced by different cell types plays distinct roles in maintaining intestinal homeostasis.


Asunto(s)
Células Epiteliales/inmunología , Interleucinas/inmunología , Mucosa Intestinal/inmunología , Linfocitos Intraepiteliales/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Femenino , Homeostasis/inmunología , Masculino , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Transducción de Señal/inmunología
9.
J Exp Med ; 218(2)2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33125052

RESUMEN

During thymocyte development, medullary thymic epithelial cells (mTECs) provide appropriate instructive cues in the thymic microenvironment for not only negative selection but also the generation of regulatory T (T reg) cells. Here, we identify that miR-155, a microRNA whose expression in T reg cells has previously been shown to be crucial for their development and homeostasis, also contributes to thymic T reg (tT reg) cell differentiation by promoting mTEC maturation. Mechanistically, we show that RANKL stimulation induces expression of miR-155 to safeguard the thymic medulla through targeting multiple known and previously uncharacterized molecules within the TGFß signaling pathway, which is recognized for its role in restricting the maturation and expansion of mTECs. Our work uncovers a miR-155-TGFß axis in the thymic medulla to determine mTEC maturity and, consequently, the quantity of tT reg cells and suggests that miR-155 ensures proper tT reg cell development in both cell-intrinsic and -extrinsic manners.


Asunto(s)
Células Epiteliales/inmunología , MicroARNs/inmunología , Linfocitos T Reguladores/inmunología , Timo/inmunología , Animales , Diferenciación Celular/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Transducción de Señal/inmunología , Factor de Crecimiento Transformador beta/inmunología
10.
J Exp Med ; 199(1): 91-8, 2004 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-14707116

RESUMEN

Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this alpha-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor-immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA-/- mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.


Asunto(s)
Células de la Médula Ósea/citología , Supervivencia Celular/fisiología , Células Plasmáticas/citología , Receptores del Factor de Necrosis Tumoral/fisiología , Animales , Factor Activador de Células B , Antígeno de Maduración de Linfocitos B , Secuencia de Bases , Células de la Médula Ósea/fisiología , Cartilla de ADN , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Células Plasmáticas/fisiología , Receptores del Factor de Necrosis Tumoral/deficiencia , Receptores del Factor de Necrosis Tumoral/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/deficiencia , Factor de Necrosis Tumoral alfa/fisiología
11.
Sci Adv ; 5(12): eaaw1715, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31844658

RESUMEN

Follicular helper T (TFH) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating TFH cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated TFH cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced TFH cell responses. Mechanistically, miR-23~27~24 clusters coordinately control TFH cells through targeting a network of genes that are crucial for TFH cell biology. Among them, thymocyte selection-associated HMG-box protein (TOX) was identified as a central transcription regulator in TFH cell development. TOX is highly up-regulated in both mouse and human TFH cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in TFH cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal TFH cell responses for resultant humoral immunity.


Asunto(s)
Diferenciación Celular/genética , Inmunidad Humoral/genética , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T/inmunología , Animales , Regulación del Desarrollo de la Expresión Génica/inmunología , Proteínas del Grupo de Alta Movilidad/genética , Humanos , Inmunidad Humoral/inmunología , Activación de Linfocitos/inmunología , Ratones , MicroARNs/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Transducción de Señal , Linfocitos T Colaboradores-Inductores/metabolismo
12.
Nat Commun ; 9(1): 2757, 2018 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-30013024

RESUMEN

Reciprocal interactions between B and follicular T helper (Tfh) cells orchestrate the germinal center (GC) reaction, a hallmark of humoral immunity. Abnormal GC responses could lead to the production of pathogenic autoantibodies and the development of autoimmunity. Here we show that miR-146a controls GC responses by targeting multiple CD40 signaling pathway components in B cells; by contrast, loss of miR-146a in T cells does not alter humoral responses. However, specific deletion of both miR-146a and its paralog, miR-146b, in T cells increases Tfh cell numbers and enhanced GC reactions. Thus, our data reveal differential cell-intrinsic regulations of GC B and Tfh cells by miR-146a and miR-146b. Together, members of the miR-146 family serve as crucial molecular brakes to coordinately control GC reactions to generate protective humoral responses without eliciting unwanted autoimmunity.


Asunto(s)
Linfocitos B/inmunología , Centro Germinal/inmunología , MicroARNs/genética , Transducción de Señal/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Autoanticuerpos/biosíntesis , Autoinmunidad/genética , Linfocitos B/citología , Linfocitos B/efectos de los fármacos , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Antígenos CD40/genética , Antígenos CD40/inmunología , Diferenciación Celular , Regulación de la Expresión Génica , Centro Germinal/citología , Centro Germinal/efectos de los fármacos , Inmunidad Humoral/genética , Interleucina-4/farmacología , Ratones , Ratones Transgénicos , MicroARNs/inmunología , Cultivo Primario de Células , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/efectos de los fármacos
13.
J Clin Invest ; 127(2): 530-542, 2017 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-28067667

RESUMEN

MicroRNAs (miRs) are tightly regulated in the immune system, and aberrant expression of miRs often results in hematopoietic malignancies and autoimmune diseases. Previously, it was suggested that elevated levels of miR-27 in T cells isolated from patients with multiple sclerosis facilitate disease progression by inhibiting Th2 immunity and promoting pathogenic Th1 responses. Here we have demonstrated that, although mice with T cell-specific overexpression of miR-27 harbor dysregulated Th1 responses and develop autoimmune pathology, these disease phenotypes are not driven by miR-27 in effector T cells in a cell-autonomous manner. Rather, dysregulation of Th1 responses and autoimmunity resulted from a perturbed Treg compartment. Excessive miR-27 expression in murine T cells severely impaired Treg differentiation. Moreover, Tregs with exaggerated miR-27-mediated gene regulation exhibited diminished homeostasis and suppressor function in vivo. Mechanistically, we determined that miR-27 represses several known as well as previously uncharacterized targets that play critical roles in controlling multiple aspects of Treg biology. Collectively, our data show that miR-27 functions as a key regulator in Treg development and function and suggest that proper regulation of miR-27 is pivotal to safeguarding Treg-mediated immunological tolerance.


Asunto(s)
Diferenciación Celular/inmunología , Regulación de la Expresión Génica/inmunología , Tolerancia Inmunológica , MicroARNs/inmunología , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular/genética , Ratones , Ratones Transgénicos , MicroARNs/genética , Células TH1/inmunología , Células Th2/inmunología
14.
J Exp Med ; 213(2): 235-49, 2016 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-26834155

RESUMEN

Coordinated repression of gene expression by evolutionarily conserved microRNA (miRNA) clusters and paralogs ensures that miRNAs efficiently exert their biological impact. Combining both loss- and gain-of-function genetic approaches, we show that the miR-23∼27∼24 clusters regulate multiple aspects of T cell biology, particularly helper T (Th) 2 immunity. Low expression of this miRNA family confers proper effector T cell function at both physiological and pathological settings. Further studies in T cells with exaggerated regulation by individual members of the miR-23∼27∼24 clusters revealed that miR-24 and miR-27 collaboratively limit Th2 responses through targeting IL-4 and GATA3 in both direct and indirect manners. Intriguingly, although overexpression of the entire miR-23 cluster also negatively impacts other Th lineages, enforced expression of miR-24, in contrast to miR-23 and miR-27, actually promotes the differentiation of Th1, Th17, and induced regulatory T cells, implying that under certain conditions, miRNA families can fine tune the biological effects of their regulation by having individual members antagonize rather than cooperate with each other. Together, our results identify a miRNA family with important immunological roles and suggest that tight regulation of miR-23∼27∼24 clusters in T cells is required to maintain optimal effector function and to prevent aberrant immune responses.


Asunto(s)
MicroARNs/genética , MicroARNs/inmunología , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Animales , Asma/genética , Asma/inmunología , Asma/patología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Modelos Animales de Enfermedad , Factor de Transcripción GATA3/biosíntesis , Factor de Transcripción GATA3/genética , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Interleucina-4/biosíntesis , Interleucina-4/genética , Activación de Linfocitos/genética , Ratones , Ratones Transgénicos , Familia de Multigenes , Fenotipo , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Células Th2/citología , Células Th2/inmunología
15.
Zhongguo Gu Shang ; 21(8): 626-8, 2008 Aug.
Artículo en Zh | MEDLINE | ID: mdl-19108384

RESUMEN

OBJECTIVE: To study the therapeutic effect of combined multifunctional external fixator for treatment of tibiofibular fracture. METHODS: From Oct 1999 to Apr 2006, 37 patients of tibiofibular fractures were treated with combined multifunctional external fixator. There were 28 males and 9 females with an average of 47.8 years (range,from 22 to 76 years). There were 7 cases with transverse fracture, 18 comminuted fracture, 8 spiral fracture and 4 oblique fracture;closed fracture was in 29 cases and open fracture was in 8. RESULTS: All the patients were followed up 6 to 13 months (mean,9 months)and achieved union of the fractures. CONCLUSION: Combined multifunctional external fixator for tibiofibular fracture has many advantages such as minimal invasion, convenient operation, reliable fixation and high union ratio of fracture. Moreover,the treatment has no influence on motion of knee and ankle joint, even patient can walk with external fixator without long-term bed rest.


Asunto(s)
Fijadores Externos , Peroné/lesiones , Fracturas de la Tibia/cirugía , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad
16.
Blood ; 110(1): 193-200, 2007 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-17360936

RESUMEN

The recruitment of tumor necrosis factor receptor-associated factors (TRAFs) 1, 2, 3, 5, and 6 to the CD40 cytoplasmic tail upon CD40 trimerization results in downstream signaling events that ultimately lead to CD40-dependent, thymus-dependent (TD) humoral immune responses. Previously, we have shown signaling through the C-terminal tail of CD40 in the absence of canonical TRAF-binding sites is capable of signaling through an alternative TRAF2-binding site. Here, we demonstrate that B cells from mice harboring CD40 with only the C-terminal tail can activate both canonical and noncanonical NFkappaB signaling pathways. Moreover, while lacking germinal center formation, several hallmarks of humoral immune responses including clonal B-cell activation/expansion, antibody isotype switching, and affinity maturation remain normal. This study demonstrates a new functional domain in CD40 that controls critical aspects of B-cell immunity in an in vivo setting.


Asunto(s)
Linfocitos B/citología , Antígenos CD40/fisiología , Factor 2 Asociado a Receptor de TNF/metabolismo , Animales , Formación de Anticuerpos , Sitios de Unión , Antígenos CD40/química , Antígenos CD40/inmunología , Diferenciación Celular , Proliferación Celular , Ratones , FN-kappa B/metabolismo , Transducción de Señal
17.
Proc Natl Acad Sci U S A ; 100(22): 12905-10, 2003 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-14555759

RESUMEN

The coordinated regulation of chemokine responsiveness plays a critical role in the development of humoral immunity. After antigen challenge and B cell activation, the emerging plasma cells (PCs) undergo CXCL12-induced chemotaxis to the bone marrow, where they produce Ab and persist. Here we show that PCs, but not B cells or T cells from lupus-prone NZM mice, are deficient in CXCL12-induced migration. PC unresponsiveness to CXCL12 results in a marked accumulation of PCs in the spleen of mice, and a concordant decrease in bone marrow PCs. Unlike normal mice, in NZM mice, a majority of the splenic PCs are long-lived. This deficiency is a consequence of the genetic interactions of multiple systemic lupus erythematosus susceptibility loci.


Asunto(s)
Células de la Médula Ósea/inmunología , Quimiocinas CXC/fisiología , Células Plasmáticas/inmunología , Receptores Mensajeros de Linfocitos/inmunología , Traslado Adoptivo , Animales , Quimiocina CXCL12 , Quimiocinas CXC/deficiencia , Quimiocinas CXC/genética , Quimiotaxis de Leucocito , Susceptibilidad a Enfermedades/inmunología , Ensayo de Inmunoadsorción Enzimática , Inmunohistoquímica , Lupus Eritematoso Sistémico/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Células Plasmáticas/fisiología , Bazo/inmunología
18.
J Biol Chem ; 278(46): 45414-8, 2003 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-12960157

RESUMEN

Tumor necrosis factor receptor-associated factors (TRAFs) belong to a family of adapter proteins that are involved in tumor necrosis factor receptor superfamily signaling. It has been shown that the recruitment of TRAFs to the CD40 cytoplasmic tail is essential for CD40-mediated B cell responses. However, it has also been shown that some early B cell responses, such as up-regulation of cell surface molecules and B cell proliferation are only marginally impaired by the disruption of previously defined TRAF binding sites (Ahonen, C., Manning, E., Erickson, L. D., O'Connor, B. P., Lind, E. F., Pullen, S. S., Kehry, M. R., and Noelle, R. J. (2002) Nat. Immunol. 3, 451-456; and Manning, E., Pullen, S. S., Souza, D. J., Kehry, M., and Noelle, R. J. (2002) Eur. J. Immunol. 32, 39-49). In this report, we identify a second TRAF2 binding site in the CD40 C terminus. The binding motif "SVQE" fits into the major TRAF2 binding consensus sequence, and its disruption resulted in the loss of remaining CD40 functions. Hence, like CD30, the CD40 cytoplasmic tail contains two distinct and functionally important TRAF2 binding sites.


Asunto(s)
Antígenos CD40/metabolismo , Proteínas/metabolismo , Transducción de Señal , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Sitios de Unión , Western Blotting , Ligando de CD40/biosíntesis , División Celular , Línea Celular , Citoplasma/metabolismo , ADN/metabolismo , Antígeno Ki-1/biosíntesis , Ratones , Modelos Genéticos , Datos de Secuencia Molecular , Mutación , Pruebas de Precipitina , Unión Proteica , Estructura Terciaria de Proteína , Factor 2 Asociado a Receptor de TNF , Transfección , Técnicas del Sistema de Dos Híbridos , Regulación hacia Arriba
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