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1.
Nat Immunol ; 22(1): 67-73, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33169014

RESUMEN

Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fcγ receptor FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1.


Asunto(s)
COVID-19/inmunología , Citocinas/inmunología , Inmunoglobulina G/inmunología , Receptores de IgG/inmunología , SARS-CoV-2/inmunología , Adolescente , Adulto , Anciano , COVID-19/metabolismo , COVID-19/virología , Niño , Citocinas/metabolismo , Femenino , Glicosilación , Humanos , Inmunoglobulina G/metabolismo , Interleucina-6 , Masculino , Persona de Mediana Edad , Receptores de IgG/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
2.
J Allergy Clin Immunol ; 150(4): 972-978.e7, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35487308

RESUMEN

BACKGROUND: Clinical studies of type 2 (T2) cytokine-related neutralizing antibodies in asthma have identified a substantial subset of patients with low levels of T2 inflammation who do not benefit from T2 cytokine neutralizing antibody treatment. Non-T2 mechanisms are poorly understood in asthma but represent a redefined unmet medical need. OBJECTIVE: We sought to gain a better understanding of genetic contributions to T2-low asthma. METHODS: We utilized an unbiased genome-wide association study of patients with moderate to severe asthma stratified by T2 serum biomarker periostin. We also performed additional expression and biological analysis for the top genetic hits. RESULTS: We identified a novel protective single nucleotide polymorphism at chr19q13.41, which is selectively associated with T2-low asthma and establishes Kallikrein-related peptidase 5 (KLK5) as the causal gene mediating this association. Heterozygous carriers of the single nucleotide polymorphisms have reduced KLK5 expression. KLK5 is secreted by human bronchial epithelial cells and elevated in asthma bronchial alveolar lavage. T2 cytokines IL-4 and IL-13 downregulate KLK5 in human bronchial epithelial cells. KLK5, dependent on its catalytic function, induces epithelial chemokine/cytokine expression. Finally, overexpression of KLK5 in airway or lack of an endogenous KLK5 inhibitor, SPINK5, leads to spontaneous airway neutrophilic inflammation. CONCLUSION: Our data identify KLK5 to be the causal gene at a novel locus at chr19q13.41 associated with T2-low asthma.


Asunto(s)
Asma , Estudio de Asociación del Genoma Completo , Anticuerpos Neutralizantes/genética , Asma/genética , Quimiocinas/genética , Citocinas/metabolismo , Humanos , Inflamación/genética , Interleucina-13/genética , Interleucina-4/genética , Calicreínas/genética , Calicreínas/metabolismo
3.
J Allergy Clin Immunol ; 146(5): 1121-1136.e9, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32179158

RESUMEN

BACKGROUND: Bcl6 is required for the development of T follicular helper cells and T follicular regulatory (Tfr) cells that regulate germinal center responses. Bcl6 also affects the function of regulatory T (Treg) cells. OBJECTIVE: The goal of this study was to define the functions of Bcl6 in Treg cells, including Tfr cells, in the context of allergic airway inflammation. METHODS: We used a model of house dust mite sensitization to challenge wild-type, Bcl6fl/fl Foxp3-Cre, and Prdm1 (Blimp1)fl/fl Foxp3-Cre mice to study the reciprocal roles of Bcl6 and Blimp1 in allergic airway inflammation. RESULTS: In the house dust mite model, Tfr cells repress the production of IgE and Bcl6+ Treg cells suppress the generation of type 2 cytokine-producing cells in the lungs. In mice with Bcl6-deficient Treg cells, twice as many ST2+ (IL-33R+) Treg cells develop as are observed in wild-type mice. ST2+ Treg cells in the context of allergic airway inflammation are Blimp1 dependent, express type 2 cytokines, and share features of visceral adipose tissue Treg cells. Bcl6-deficient Treg cells are more susceptible, and Blimp1-deficient Treg cells are resistant, to acquiring the ST2+ Treg-cell phenotype in vitro and in vivo in response to IL-33. Bcl6-deficient ST2+ Treg cells, but not Bcl6-deficient ST2+ conventional T cells, strongly promote allergic airway inflammation when transferred into recipient mice. Lastly, ST2 is required for the exacerbated allergic airway inflammation in Bcl6fl/fl Foxp3-Cre mice. CONCLUSIONS: During allergic airway inflammation, Bcl6 and Blimp1 play dual roles in regulating Tfr-cell activity in the germinal center and in the development of ST2+ Treg cells that promote type 2 cytokine responses.


Asunto(s)
Centro Germinal/inmunología , Hipersensibilidad/inmunología , Neumonía/inmunología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Linfocitos T Reguladores/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Antígenos Dermatofagoides/inmunología , Diferenciación Celular , Células Cultivadas , Citocinas/metabolismo , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Pyroglyphidae
4.
Immunol Cell Biol ; 98(8): 617-619, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32632971

RESUMEN

Shade et al. demonstrate that people with peanut allergies produce IgE antibodies that are enriched for sialic acid-containing glycoforms. The sialylated IgE triggered significantly more degranulation by basophils and mast cells, suggesting intrinsic functional differences between IgEs from allergic and nonallergic subjects.


Asunto(s)
Inmunoglobulina E , Hipersensibilidad al Cacahuete , Basófilos , Humanos , Mastocitos , Virulencia
5.
Eur J Immunol ; 47(7): 1136-1141, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28586108

RESUMEN

The transcription factors Bcl6 and Blimp1 have opposing roles in the development of the follicular helper T (TFH ) cells: Bcl6 promotes and Blimp1 inhibits TFH -cell differentiation. Similarly, Bcl6 activates, while Blimp1 represses, expression of the TFH -cell marker PD-1. However, Bcl6 and Blimp1 repress each other's expression, complicating the interpretation of the regulatory network. Here we sought to clarify the extent to which Bcl6 and Blimp1 independently control TFH -cell differentiation by generating mice with T-cell specific deletion of both Bcl6 and Blimp1 (double conditional KO [dcKO] mice). Our data indicate that Blimp1 does not control TFH -cell differentiation independently of Bcl6. However, a population of T follicular regulatory (TFR ) cells developed independently of Bcl6 in dcKO mice. We have also analyzed regulation of IL-10 and PD-1, two genes controlled by both Bcl6 and Blimp1, and observed that Bcl6 regulates both genes independently of Blimp1. We found that Bcl6 positively regulates PD-1 expression by inhibiting the ability of T-bet/Tbx21 to repress Pdcd1 transcription. Our data provide a novel mechanism for positive control of gene expression by Bcl6, and illuminate how Bcl6 and Blimp1 control TFH -cell differentiation.


Asunto(s)
Diferenciación Celular , Receptor de Muerte Celular Programada 1/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Factores de Transcripción/metabolismo , Animales , Expresión Génica , Regulación de la Expresión Génica , Centro Germinal/inmunología , Interleucina-10/genética , Interleucina-10/inmunología , Activación de Linfocitos , Ratones , Ratones Noqueados , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Receptor de Muerte Celular Programada 1/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/deficiencia , Proteínas Proto-Oncogénicas c-bcl-6/genética , Transducción de Señal , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunología , Proteínas de Dominio T Box/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/fisiología , Factores de Transcripción/deficiencia , Factores de Transcripción/genética
6.
Cell Rep Med ; 4(8): 101130, 2023 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-37490914

RESUMEN

Signal regulatory protein (SIRPα) is an immune inhibitory receptor expressed by myeloid cells to inhibit immune cell phagocytosis, migration, and activation. Despite the progress of SIRPα and CD47 antagonist antibodies to promote anti-cancer immunity, it is not yet known whether SIRPα receptor agonism could restrain excessive autoimmune tissue inflammation. Here, we report that neutrophil- and monocyte-associated genes including SIRPA are increased in inflamed tissue biopsies from patients with rheumatoid arthritis and inflammatory bowel diseases, and elevated SIRPA is associated with treatment-refractory ulcerative colitis. We next identify an agonistic anti-SIRPα antibody that exhibits potent anti-inflammatory effects in reducing neutrophil and monocyte chemotaxis and tissue infiltration. In preclinical models of arthritis and colitis, anti-SIRPα agonistic antibody ameliorates autoimmune joint inflammation and inflammatory colitis by reducing neutrophils and monocytes in tissues. Our work provides a proof of concept for SIRPα receptor agonism for suppressing excessive innate immune activation and chronic inflammatory disease treatment.


Asunto(s)
Colitis , Neoplasias , Humanos , Fagocitosis , Neoplasias/tratamiento farmacológico , Neutrófilos/metabolismo , Inflamación/patología , Colitis/metabolismo
7.
Methods Mol Biol ; 2380: 165-174, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34802130

RESUMEN

Antibodies produced by plasma cells are a major arm of adaptive immunity. Germinal center reactions that include germinal center B cells and follicular T cells are fundamental players for antibody production, particularly antigen specific antibodies. Here we describe multiple methods that we and others have developed to analyze the production of antigen-specific antibodies in mice, with protocols for assessing antibody affinity and antibody isotype. The detection of antigen-specific IgE in serum using a traditional enzyme-linked immunosorbent assay (ELISA) method is often problematic due to much higher amounts of IgG. Thus we provide a specialized protocol for the detection of antigen-specific IgE in serum using ELISA.


Asunto(s)
Formación de Anticuerpos , Animales , Antígenos , Ensayo de Inmunoadsorción Enzimática , Inmunoglobulina E , Ratones , Linfocitos T
8.
J Exp Med ; 217(7)2020 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-32399548

RESUMEN

A Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung to inhaled but not systemically delivered allergens but is dispensable for TFH function and IgE production. Mechanistically, Blimp-1 acts through Bcl6, leading to increased GATA3 expression in lung Th2 cells. Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to up-regulate Blimp-1 and promote Th2 cell development. These data reveal a hitherto unappreciated role for an IL-10-STAT3-Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses.


Asunto(s)
Alérgenos/inmunología , Asma/inmunología , Pulmón/inmunología , Pulmón/patología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Células Th2/inmunología , Animales , Asma/complicaciones , Diferenciación Celular , Factor de Transcripción GATA3/metabolismo , Inmunoglobulina E/metabolismo , Inflamación/patología , Interleucina-6/metabolismo , Interleucinas/metabolismo , Ganglios Linfáticos/metabolismo , Ratones Endogámicos C57BL , Especificidad de Órganos , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Pyroglyphidae/inmunología , Receptores de Interleucina-21/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Linfocitos T Colaboradores-Inductores/metabolismo
9.
J Clin Invest ; 130(7): 3820-3832, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32255767

RESUMEN

Food allergies are a major clinical problem and are driven by IgE antibodies (Abs) specific for food antigens (Ags). T follicular regulatory (Tfr) cells are a specialized subset of FOXP3+ T cells that modulate Ab responses. Here, we analyzed the role of Tfr cells in regulating Ag-specific IgE using a peanut-based food allergy model in mice. Peanut-specific IgE titers and anaphylaxis responses were significantly blunted in Tfr cell-deficient Foxp3-Cre Bcl6fl/fl mice. Loss of Tfr cells led to greatly increased nonspecific IgE levels, showing that Tfr cells have both helper and suppressor functions in IgE production in the germinal center (GC) that work together to facilitate the production of Ag-specific IgE. Foxp3-Cre Ptenfl/fl mice with augmented Tfr cell responses had markedly higher levels of peanut-specific IgE, revealing an active helper function by Tfr cells on Ag-specific IgE. The helper function of Tfr cells for IgE production involves IL-10, and the loss of IL-10 signaling by B cells led to a severely curtailed peanut-specific IgE response, decreased GCB cell survival, and loss of GC dark zone B cells after peanut sensitization. We thus reveal that Tfr cells have an unexpected helper role in promoting food allergy and may represent a target for drug development.


Asunto(s)
Hipersensibilidad a los Alimentos/inmunología , Alimentos , Centro Germinal/inmunología , Inmunoglobulina E/inmunología , Interleucina-10/inmunología , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Hipersensibilidad a los Alimentos/genética , Hipersensibilidad a los Alimentos/patología , Centro Germinal/patología , Interleucina-10/genética , Ratones , Ratones Noqueados , Transducción de Señal/genética , Linfocitos T Reguladores/patología
10.
Sci Adv ; 6(31): eabb0806, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32832688

RESUMEN

Aging results in profound immune dysfunction, resulting in the decline of vaccine responsiveness previously attributed to irreversible defects in the immune system. In addition to increased interleukin-6 (IL-6), we found aged mice exhibit increased systemic IL-10 that requires forkhead box P3-negative (FoxP3-), but not FoxP3+, CD4+T cells. Most IL-10-producing cells manifested a T follicular helper (Tfh) phenotype and required the Tfh cytokines IL-6 and IL-21 for their accrual, so we refer to them as Tfh10 cells. IL-21 was also required to maintain normal serum levels of IL-6 and IL-10. Notably, antigen-specific Tfh10 cells arose after immunization of aged mice, and neutralization of IL-10 receptor signaling significantly restored Tfh-dependent antibody responses, whereas depletion of FoxP3+ regulatory and follicular regulatory cells did not. Thus, these data demonstrate that immune suppression with age is reversible and implicate Tfh10 cells as an intriguing link between "inflammaging" and impaired immune responses with age.

11.
medRxiv ; 2020 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-32511463

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can cause Coronavirus Disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that severe COVID-19 patients produced a unique serologic signature, including increased IgG1 with afucosylated Fc glycans. This Fc modification on SARS-CoV-2 IgGs enhanced interactions with the activating FcγR, FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including IL-6 and TNF. These results show that disease severity in COVID-19 correlates with the presence of afucosylated IgG1, a pro-inflammatory IgG Fc modification.

12.
Trends Pharmacol Sci ; 40(10): 714-716, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31493932

RESUMEN

Anaphylaxis, a life-threatening allergic reaction, is dependent on high affinity allergen-specific IgE. Gowthaman et al. now show that a new interleukin (IL)-13-expressing T helper cell subset specifically promotes high-affinity IgE responses. The discovery of T follicular helper (Tfh)13 cells defines potential new targets for allergy therapies.


Asunto(s)
Anafilaxia , Interleucina-13 , Alérgenos , Humanos , Inmunoglobulina E , Linfocitos T Colaboradores-Inductores/inmunología
13.
JCI Insight ; 4(16)2019 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-31434804

RESUMEN

T follicular regulatory (TFR) cells are found in the germinal center (GC) response and help shape the antibody (Ab) response. However, the precise role of TFR cells in the GC is controversial. Here, we addressed TFR cell function using mice with impaired TFR cell development (Bcl6-flox/Foxp3-cre, or Bcl6FC mice), mice with augmented TFR cell development (Blimp1-flox/Foxp3-cre, or Blimp1FC mice), and two different methods of immunization. Unexpectedly, GC B cell levels positively correlated with TFR cell levels. Using a gene profiling approach, we found that TFH cells from TFR-deficient mice showed strong upregulation of granzyme B (Gzmb) and other effector CD8+ T cell genes, many of which were Stat4 dependent. The upregulation of cytotoxic genes was the highest in TFH cells from TFR-deficient mice where Blimp1 was also deleted in Foxp3+ regulatory T cells (Bcl6-flox/Prdm1-flox/Foxp3-cre [DKO] mice). Granzyme B- and Eomesodermin-expressing TFH cells correlated with a higher rate of apoptotic GC B cells. Klrg1+ TFH cells from DKO mice expressed higher levels of Gzmb. Our data show that TFR cells repress the development of abnormal cytotoxic TFH cells, and the presence of cytotoxic TFH cells correlates with a lower GC and Ab response. Our data show what we believe is a novel mechanism of action for TFR cells helping the GC response.


Asunto(s)
Granzimas/biosíntesis , Linfopoyesis/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Animales , Citotoxicidad Inmunológica/genética , Citotoxicidad Inmunológica/inmunología , Femenino , Expresión Génica , Centro Germinal/citología , Centro Germinal/inmunología , Granzimas/genética , Mediadores de Inflamación/metabolismo , Linfopoyesis/genética , Masculino , Ratones , Bazo/citología , Bazo/inmunología , Linfocitos T Colaboradores-Inductores/citología
14.
Immunohorizons ; 3(7): 306-316, 2019 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-31356160

RESUMEN

Autoantibodies can result from excessive T follicular helper (Tfh) cell activity, whereas T follicular regulatory (Tfr) cells negatively regulate autoantibody production. IL-2 knockout (KO) mice on the BALB/c background have elevated Tfh responses, produce autoantibodies, and develop lethal autoimmunity. We analyzed Tfh and Tfr cells in IL-2 KO mice on the C57BL/6 (B6) genetic background. In B6 IL-2 KO mice, the spontaneous formation of Tfh cells and germinal center B cells was greatly enhanced, along with production of anti-DNA autoantibodies. IL-2 has been reported to repress Tfr cell differentiation; however, Tfr cells were not increased over wild-type levels in the B6 IL-2 KO mice. To assess Tfh and Tfr cell regulation of autoantibody production in IL-2 KO mice, we generated IL-2 KO mice with a T cell-specific deletion of the master Tfh cell transcription factor Bcl6. In IL-2 KO Bcl6 conditional KO (2KO-Bcl6TC) mice, Tfh cells, Tfr cells, and germinal center B cells were ablated. In contrast to expectations, autoantibody IgG titers in 2KO-Bcl6TC mice were significantly elevated over autoantibody IgG titers in IL-2 KO mice. Specific deletion of Tfr cells with Foxp3-cre Bcl6-flox alleles in IL-2 KO mice led to early lethality, before high levels of autoantibodies could develop. We found IL-2+/+ Tfr cell-deficient mice produce significant levels of autoantibodies. Our overall findings provide evidence that Tfh cells are dispensable for high-level production of autoantibodies and also reveal a complex interplay between Tfh and Tfr cells in autoantibody production and autoimmune disease.


Asunto(s)
Autoanticuerpos/biosíntesis , Autoinmunidad/inmunología , Técnicas de Inactivación de Genes , Interleucina-2/genética , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular , Interleucina-2/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Factor 88 de Diferenciación Mieloide/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/metabolismo
15.
Front Immunol ; 9: 1536, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30013575

RESUMEN

Follicular helper T (Tfh) cells are necessary for germinal center (GC) formation and within the GC, provide key signals to B cells for their differentiation into plasmablasts and plasma cells that secrete high-affinity and isotype-switched antibody (Ab). A specialized subset of Foxp3+ T cells termed T follicular regulatory (Tfr) cells, also regulate the differentiation of Ab-secreting cells from the GC. Tfr-cell function in the GC is not well understood, however, the dominant paradigm currently is that Tfr cells repress excessive Tfh and GC B cell proliferation and help promote stringent selection of high-affinity B cells. A mouse model where the Bcl6 gene is specifically deleted in Foxp3+ T cells (Bcl6FC mice) allows the study of Tfr cell function with more precision than other approaches. Studies with this model have shown that Tfr cells play a key role in maintaining GC B cell proliferation and Ab levels. Part of the mechanism for this positive "helper" effect of Tfr cells on the GC is Tfr cell-derived IL-10, which can promote B cell growth and entry into the dark zone of the GC. Recent studies on Tfr cells support a new paradigm for Tfr cell function in the GC reaction. Here, we review studies on Tfr cell functions and discuss the evidence that Tfr cells can have a major helper role in the GC-dependent Ab response.

16.
Mol Immunol ; 81: 67-75, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27898346

RESUMEN

The transcription factor Bcl6 is a master regulator of follicular helper T (TFH) cells, and understanding the signaling pathway that induces Bcl6 and TFH cell differentiation is therefore critical. IL-2 produced during T cell activation inhibits Bcl6 expression but how TFH cells evade IL-2 inhibition is not completely understood. Here we show that Bcl6 is highly up-regulated in activated CD4 T cells following glucose deprivation (GD), and this pathway is insensitive to inhibition by IL-2. Similar to GD, the glucose analog 2-deoxyglucose (2DG) inhibits glycolysis, and 2DG induced Bcl6 expression in activated CD4 T cells. The metabolic sensor AMP kinase (AMPK) is activated when glycolysis is decreased, and the induction of Bcl6 by GD was inhibited by the AMPK antagonist compound C. Additionally, activation of AMPK by the drug AICAR caused Bcl6 up-regulation in activated CD4 T cells. When mice were immunized with KLH using AICAR as an adjuvant, there was a strong TFH-dependent enhancement of KLH-specific antibody (Ab) responses, and higher Bcl6 expression in TFH cells in vivo. Activation of AMPK strongly induced BCL6 and the up-regulation of TFH cell marker expression by human CD4 T cells. Our data reveal a major new pathway for TFH cell differentiation, conserved by both mouse and human T cells. Mature TFH cells are reported to have a lower metabolic state compared to TH1 cells. Our data indicates that decreased metabolism may be deterministic for TFH cell differentiation, and not simply a result of TFH cell differentiation.


Asunto(s)
Adenilato Quinasa/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/biosíntesis , Adenilato Quinasa/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Activación de Linfocitos/inmunología , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-bcl-6/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa
17.
PLoS One ; 11(5): e0155040, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27148746

RESUMEN

The production of antibody is precisely controlled during the germinal center (GC) reaction. This process is dependent on the help from follicular T helper (Tfh) cells to germinal center (GC) B cells and is regulated by regulatory follicular T helper (Tfr) cells. How Tfr cells develop and how their suppressive activity functions are not well understood. Here, we found that Stat3 is indispensible for Tfr cell differentiation. After immunization with Sheep Red Blood Cells (SRBC), the loss of Tfr cells caused by deletion of Stat3 in Treg cells does not affect the size of Tfh or GC B cell population, but rather leads to strongly enhanced production of antigen-specific IgG1 and IgG2b. In Peyer's patches (PPs) in the gut, we found that Stat3 expression in Treg cells is also required for Tfr cell formation to commensal organisms. However, loss of Tfr cells in the gut did not affect the numbers of Tfh cells and GC B cells, nor affect IgG1 or IgA switching by GC B cells. Overall, our study has uncovered unique roles of Stat3 in Tfr cell differentiation and the regulation of the antibody response.


Asunto(s)
Diferenciación Celular/inmunología , Factor de Transcripción STAT3/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Animales , Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Centro Germinal/inmunología , Activación de Linfocitos/inmunología , Ratones , Ovinos/inmunología
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