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1.
Front Immunol ; 12: 731100, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603308

RESUMO

Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious infectious disease that has led to a global pandemic with high morbidity and mortality. High-affinity neutralizing antibody is important for controlling infection, which is closely regulated by follicular helper T (Tfh) cells. Tfh cells play a central role in promoting germinal center reactions and driving cognate B cell differentiation for antibody secretion. Available studies indicate a close relationship between virus-specific Tfh cell-mediated immunity and SARS-CoV-2 infection progression. Although several lines of evidence have suggested that Tfh cells contribute to the control of SARS-CoV-2 infection by eliciting neutralizing antibody productions, further studies are needed to elucidate Tfh-mediated effector mechanisms in anti-SARS-CoV-2 immunity. Here, we summarize the functional features and roles of virus-specific Tfh cells in the immunopathogenesis of SARS-CoV-2 infection and in COVID-19 vaccines, and highlight the potential of targeting Tfh cells as therapeutic strategy against SARS-CoV-2 infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Células T Auxiliares Foliculares/imunologia , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , COVID-19/patologia , Vacinas contra COVID-19/imunologia , Diferenciação Celular/imunologia , Centro Germinativo/citologia , Centro Germinativo/imunologia , Humanos , Ativação Linfocitária/imunologia , Células T Auxiliares Foliculares/citologia
2.
Nat Immunol ; 22(10): 1327-1340, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34556886

RESUMO

During the germinal center (GC) reaction, B cells undergo profound transcriptional, epigenetic and genomic architectural changes. How such changes are established remains unknown. Mapping chromatin accessibility during the humoral immune response, we show that OCT2 was the dominant transcription factor linked to differential accessibility of GC regulatory elements. Silent chromatin regions destined to become GC-specific super-enhancers (SEs) contained pre-positioned OCT2-binding sites in naive B cells (NBs). These preloaded SE 'seeds' featured spatial clustering of regulatory elements enriched in OCT2 DNA-binding motifs that became heavily loaded with OCT2 and its GC-specific coactivator OCAB in GC B cells (GCBs). SEs with high abundance of pre-positioned OCT2 binding preferentially formed long-range chromatin contacts in GCs, to support expression of GC-specifying factors. Gain in accessibility and architectural interactivity of these regions were dependent on recruitment of OCAB. Pre-positioning key regulators at SEs may represent a broadly used strategy for facilitating rapid cell fate transitions.


Assuntos
Cromatina/imunologia , Imunidade Humoral/imunologia , Transportador 2 de Cátion Orgânico/imunologia , Domínios Proteicos/imunologia , Animais , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Epigenômica/métodos , Feminino , Genômica/métodos , Centro Germinativo/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição/imunologia
4.
J Immunol ; 207(5): 1388-1400, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34380649

RESUMO

Acute viral infection generates lineage-committed Th1 and T follicular helper (Tfh) memory cells that recall their lineage-specific functions following secondary challenge with virus. However, the lineage commitment of effector and memory Th cells in vivo following protein vaccination is poorly understood. In this study, we analyzed effector and memory CD4+ T cell differentiation in mice (Mus musculus) following adjuvanted glycoprotein immunization compared with acute lymphocytic choriomeningitis virus infection. Glycoprotein immunization induced CXCR5- non-Tfh effector and memory CD4+ T cells that surprisingly had not undergone polarization toward any particular Th cell lineage but had undergone memory differentiation. However, upon challenge with virus, these Th lineage-nonpolarized memory CD4+ T cells were able to generate Th1 secondary effector cells, demonstrating their lineage plasticity. In addition, Tfh and memory Tfh cells were generated in response to protein immunization, and these cells differed from infection-induced Tfh cells by their lack of the transcription factor Tbet. Rechallenge experiments demonstrated that viral infection, but not protein immunization, during either the primary or secondary immune response, restricts the recall of Bcl6 expression and the generation of germinal center Tfh cells. Together, these data demonstrate that protein immunization generates a combination of nonpolarized memory cells that are highly plastic and memory Tfh cells that can undergo further Th1-like modulation during a secondary response to viral infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Centro Germinativo/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Subpopulações de Linfócitos T/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Plasticidade Celular , Células Cultivadas , Imunização , Memória Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Vacinação
5.
J Immunol ; 207(5): 1478-1492, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34389622

RESUMO

Stable, long-term culture of primary B lymphocytes has many potential scientific and medical applications, but remains an elusive feat. A major obstacle to long-term culture is that in vitro mitogens quickly drive B cells to differentiate into short-lived plasma cells (PCs). PC differentiation is governed by opposing teams of transcription factors: Pax5, Bach2, and Bcl6 suppress PC commitment, whereas IFN regulatory factor 4 and Blimp1 promote it. To determine whether transcriptional programming could prolong B cell culture by blocking PC commitment, we generated mouse primary B cells harboring gain- or loss-of-function in the key transcription factors, continuously stimulated these cells with CD154 and IL-21, and determined growth potential and phenotypes in vitro. We found that transgenic expression of Bach2 prohibits PC commitment and endows B cells with extraordinary growth potential in response to external proliferation and survival cues. Long-term Bach2-transgenic B cell lines have genetically stable BCRs [i.e., do not acquire V(D)J mutations], express high levels of MHC class II and molecules for costimulation of T cells, and transduce intracellular signals when incubated with BCR ligands. Silencing the Bach2 transgene in an established transgenic cell line causes the cells to secrete large quantities of Ig. This system has potential applications in mAb production, BCR signaling studies, Ag presentation to T cells, and ex vivo clonal expansion for adoptive cell transfer. Additionally, our results provide insight into molecular control over activated B cell fate and suggest that forced Bach2 expression in vivo may augment germinal center B cell or memory B cell differentiation at the expense of PC commitment.


Assuntos
Linfócitos B/imunologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Centro Germinativo/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Regulação da Expressão Gênica , Memória Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Fator de Transcrição PAX5/genética , Fator de Transcrição PAX5/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo
6.
Science ; 373(6552)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34437125

RESUMO

Germinal centers (GCs) are the site of immunoglobulin somatic hypermutation and affinity maturation, processes essential to an effective antibody response. The formation of GCs has been studied in detail, but less is known about what leads to their regression and eventual termination, factors that ultimately limit the extent to which antibodies mature within a single reaction. We show that contraction of immunization-induced GCs is immediately preceded by an acute surge in GC-resident Foxp3+ T cells, attributed at least partly to up-regulation of the transcription factor Foxp3 by T follicular helper (TFH) cells. Ectopic expression of Foxp3 in TFH cells is sufficient to decrease GC size, implicating the natural up-regulation of Foxp3 by TFH cells as a potential regulator of GC lifetimes.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Fatores de Transcrição Forkhead/genética , Centro Germinativo/imunologia , Células T Auxiliares Foliculares/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD4-Positivos/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Genes Codificadores dos Receptores de Linfócitos T , Centro Germinativo/citologia , Imunização , Imunofenotipagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Célula Única , Células T Auxiliares Foliculares/imunologia , Linfócitos T Reguladores/fisiologia , Regulação para Cima
7.
Elife ; 102021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34402793

RESUMO

Follicular T helper cells (Tfh) are a specialized subset of CD4 effector T cells that are crucial for germinal center (GC) reactions and for selecting B cells to undergo affinity maturation. Despite this central role for humoral immunity, only few data exist about their clonal distribution when multiple lymphoid organs are exposed to the same antigen (Ag) as it is the case in autoimmunity. Here, we used an autoantibody-mediated disease model of the skin and injected one auto-Ag into the two footpads of the same mouse and analyzed the T cell receptor (TCR)ß sequences of Tfh located in GCs of both contralateral draining lymph nodes. We found that over 90% of the dominant GC-Tfh clonotypes were shared in both lymph nodes but only transiently. The initially dominant Tfh clonotypes especially declined after establishment of chronic disease while GC reaction and autoimmune disease continued. Our data demonstrates a dynamic behavior of Tfh clonotypes under autoimmune conditions and emphasizes the importance of the time point for distinguishing auto-Ag-specific Tfh clonotypes from potential bystander activated ones.


Assuntos
Autoanticorpos/imunologia , Autoimunidade/imunologia , Centro Germinativo/imunologia , Linfonodos/imunologia , Células T Auxiliares Foliculares/imunologia , Animais , Antígenos/administração & dosagem , Antígenos/imunologia , Linfócitos B/imunologia , Feminino , Imunidade Humoral , Imunização , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos C57BL
8.
Immunity ; 54(9): 2159-2166.e6, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34464596

RESUMO

The emergence of SARS-CoV-2 antigenic variants with increased transmissibility is a public health threat. Some variants show substantial resistance to neutralization by SARS-CoV-2 infection- or vaccination-induced antibodies. Here, we analyzed receptor binding domain-binding monoclonal antibodies derived from SARS-CoV-2 mRNA vaccine-elicited germinal center B cells for neutralizing activity against the WA1/2020 D614G SARS-CoV-2 strain and variants of concern. Of five monoclonal antibodies that potently neutralized the WA1/2020 D614G strain, all retained neutralizing capacity against the B.1.617.2 variant, four also neutralized the B.1.1.7 variant, and only one, 2C08, also neutralized the B.1.351 and B.1.1.28 variants. 2C08 reduced lung viral load and morbidity in hamsters challenged with the WA1/2020 D614G, B.1.351, or B.1.617.2 strains. Clonal analysis identified 2C08-like public clonotypes among B cells responding to SARS-CoV-2 infection or vaccination in 41 out of 181 individuals. Thus, 2C08-like antibodies can be induced by SARS-CoV-2 vaccines and mitigate resistance by circulating variants of concern.


Assuntos
Anticorpos Monoclonais/metabolismo , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/metabolismo , Linfócitos B/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Centro Germinativo/imunologia , Pulmão/virologia , SARS-CoV-2/fisiologia , Animais , Células Cultivadas , Células Clonais , Cricetinae , Modelos Animais de Doenças , Humanos , Testes de Neutralização , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Carga Viral
9.
Immunity ; 54(8): 1807-1824.e14, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34380064

RESUMO

The transcription factor forkhead box O1 (FOXO1), which instructs the dark zone program to direct germinal center (GC) polarity, is typically inactivated by phosphatidylinositol 3-kinase (PI3K) signals. Here, we investigated how FOXO1 mutations targeting this regulatory axis in GC-derived B cell non-Hodgkin lymphomas (B-NHLs) contribute to lymphomagenesis. Examination of primary B-NHL tissues revealed that FOXO1 mutations and PI3K pathway activity were not directly correlated. Human B cell lines bearing FOXO1 mutations exhibited hyperactivation of PI3K and Stress-activated protein kinase (SAPK)/Jun amino-terminal kinase (JNK) signaling, and increased cell survival under stress conditions as a result of alterations in FOXO1 transcriptional affinities and activation of transcriptional programs characteristic of GC-positive selection. When modeled in mice, FOXO1 mutations conferred competitive advantage to B cells in response to key T-dependent immune signals, disrupting GC homeostasis. FOXO1 mutant transcriptional signatures were prevalent in human B-NHL and predicted poor clinical outcomes. Thus, rather than enforcing FOXO1 constitutive activity, FOXO1 mutations enable co-option of GC-positive selection programs during the pathogenesis of GC-derived lymphomas.


Assuntos
Linfócitos B/citologia , Proteína Forkhead Box O1/genética , Centro Germinativo/imunologia , Linfoma de Células B/patologia , Animais , Linfócitos B/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular , Proliferação de Células/genética , Sobrevivência Celular/genética , Regulação da Expressão Gênica/genética , Células HEK293 , Humanos , Linfoma de Células B/genética , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia
10.
Immunity ; 54(8): 1652-1664, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34380063

RESUMO

Germinal center (GC) B cells are the source of the high-affinity, class-switched antibodies required for protective immunity. The unique biology of GC B cells involves iterative rounds of antibody gene somatic hypermutation coupled to multiple selection and differentiation pathways. Recent advances in areas such as single cell and gene editing technologies have shed new light upon these complex and dynamic processes. We review these findings here and integrate them into the current understanding of GC B cell replication and death, the retention of high-affinity and class-switched B cells in the GC, and differentiation into plasma and memory cell effectors. We also discuss how the biology of GC responses relates to vaccine effectiveness and outline current and future challenges in the field.


Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Centro Germinativo/citologia , Centro Germinativo/imunologia , Switching de Imunoglobulina/imunologia , Afinidade de Anticorpos/imunologia , Proliferação de Células , Humanos , Memória Imunológica/imunologia , Hipermutação Somática de Imunoglobulina/imunologia , Vacinação
11.
J Immunol ; 207(6): 1513-1521, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34400521

RESUMO

B cells have been implicated in the pathogenesis of multiple sclerosis, but the mechanisms that guide B cell activation in the periphery and subsequent migration to the CNS remain incompletely understood. We previously showed that systemic inflammation induces an accumulation of B cells in the spleen in a CCR6/CCL20-dependent manner. In this study, we evaluated the role of CCR6/CCL20 in the context of myelin oligodendrocyte glycoprotein (MOG) protein-induced (B cell-dependent) experimental autoimmune encephalomyelitis (EAE). We found that CCR6 is upregulated on murine B cells that migrate into the CNS during neuroinflammation. In addition, human B cells that migrate across CNS endothelium in vitro were found to be CCR6+, and we detected CCL20 production by activated CNS-derived human endothelial cells as well as a systemic increase in CCL20 protein during EAE. Although mice that lack CCR6 expression specifically on B cells exhibited an altered germinal center reaction in response to MOG protein immunization, CCR6-deficient B cells did not exhibit any competitive disadvantage in their migration to the CNS during EAE, and the clinical and pathological presentation of EAE induced by MOG protein was unaffected. These data, to our knowledge, provide new information on the role of B cell-intrinsic CCR6 expression in a B cell-dependent model of neuroinflammation.


Assuntos
Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/imunologia , Centro Germinativo/imunologia , Imunização/métodos , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Receptores CCR6/deficiência , Animais , Linfócitos B/metabolismo , Doadores de Sangue , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Células Cultivadas , Quimiocina CCL20/metabolismo , Encefalomielite Autoimune Experimental/induzido quimicamente , Células Endoteliais/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/genética , Receptores CCR6/genética , Proteínas Recombinantes/administração & dosagem
12.
Nat Immunol ; 22(9): 1127-1139, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34413521

RESUMO

Follicular helper T (TFH) cells are a specialized subset of CD4+ T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The regulation of TFH cell survival remains unclear. Here we report that TFH cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for TFH cell survival. The deletion of GPX4 in T cells selectively abrogated TFH cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased TFH cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium-GPX4-ferroptosis axis in regulating TFH homeostasis, which can be targeted to enhance TFH cell function in infection and following vaccination.


Assuntos
Ferroptose/fisiologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Selênio/farmacologia , Células T Auxiliares Foliculares/fisiologia , Adolescente , Adulto , Animais , Sobrevivência Celular/imunologia , Criança , Feminino , Centro Germinativo/citologia , Centro Germinativo/imunologia , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Imunidade Humoral/imunologia , Vacinas contra Influenza/imunologia , Peroxidação de Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/fisiologia , Ovalbumina , Células T Auxiliares Foliculares/imunologia , Vacinação , Adulto Jovem
13.
Front Immunol ; 12: 615859, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220794

RESUMO

Purpose: Systemic lupus erythematosus (SLE) is a serious autoimmune disease. Its molecular pathogenesis, especially the long non-coding RNA (lncRNA) function, remains unclear. We want to investigate the lncRNA dysregulation profile and their molecular mechanisms in SLE. Methods: In this study, we analyzed the transcriptome profiles (RNA-seq) of peripheral blood mononuclear cells (PBMCs) from SLE patients and two published transcriptome datasets to explore lncRNA profiles. The differentially expressed lncRNAs were confirmed by quantitative real-time PCR in another set of female patients. We constructed the lncRNA-mRNA regulatory networks by performing weighted gene co-expression network analysis (WGCNA). Dysregulated lncRNA AC007278.2 was repressed by short hairpin RNA (shRNA) in Jurkat cells. Dual-luciferase reporter gene assay was performed to investigate the regulatory mechanism of AC007278.2 on target gene CCR7. Results: We observed dominant up-regulation of transcripts, including mRNAs and lncRNAs, in SLE patients. By WGCNA method, we identified three modules that were highly related to SLE. We then focused on one lncRNA, AC007278.2, with a T-helper 1 lineage-specific expression pattern. We observed consistently higher AC007278.2 expression in SLE patients. Co-expression network revealed that AC007278.2 participated in the innate immune response and inflammatory bowel disease pathways. By knocking down AC007278.2 expression, we found that AC007278.2 could regulate the expression of inflammatory and cytokine stimulus response-related genes, including CCR7, AZU1, and TNIP3. AC007278.2 inhibits the functional CCR7 promoter to repress its transcription, thereby regulating autoimmunity and follicular T-helper cell differentiation. Conclusion: In summary, our study indicated the important regulatory role of lncRNAs in SLE. AC007278.2 may be treated as a novel biomarker for SLE diagnosis and treatment.


Assuntos
Centro Germinativo/imunologia , Lúpus Eritematoso Sistêmico/genética , RNA Longo não Codificante/genética , Receptores CCR7/metabolismo , Células Th1/fisiologia , Autoimunidade/genética , Diferenciação Celular , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Marcadores Genéticos/genética , Humanos , Células Jurkat , Lúpus Eritematoso Sistêmico/diagnóstico , RNA Interferente Pequeno/genética , Receptores CCR7/genética , Transcriptoma , Regulação para Cima
14.
Front Immunol ; 12: 690416, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276680

RESUMO

The AID (activation-induced cytidine deaminase)/APOBEC (apolipoprotein B mRNA editing enzyme catalytic subunit) family with its multifaceted mode of action emerges as potent intrinsic host antiviral system that acts against a variety of DNA and RNA viruses including coronaviruses. All family members are cytosine-to-uracil deaminases that either have a profound role in driving a strong and specific humoral immune response (AID) or restricting the virus itself by a plethora of mechanisms (APOBECs). In this article, we highlight some of the key aspects apparently linking the AID/APOBECs and SARS-CoV-2. Among those is our discovery that APOBEC4 shows high expression in cell types and anatomical parts targeted by SARS-CoV-2. Additional focus is given by us to the lymphoid structures and AID as the master regulator of germinal center reactions, which result in antibody production by plasma and memory B cells. We propose the dissection of the AID/APOBECs gene signature towards decisive determinants of the patient-specific and/or the patient group-specific antiviral response. Finally, the patient-specific mapping of the AID/APOBEC polymorphisms should be considered in the light of COVID-19.


Assuntos
Desaminase APOBEC-1/genética , COVID-19/enzimologia , COVID-19/imunologia , Citidina Desaminase/genética , SARS-CoV-2/genética , Transcriptoma , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , COVID-19/virologia , Centro Germinativo/imunologia , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade Humoral/genética , Plasmócitos/imunologia , Polimorfismo Genético , Edição de RNA/genética , RNA Viral/genética
16.
J Immunol ; 207(4): 1018-1032, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34330755

RESUMO

Germinal center reactions are established during a thymus-dependent immune response. Germinal center (GC) B cells are rapidly proliferating and undergo somatic hypermutation in Ab genes. This results in the production of high-affinity Abs and establishment of long-lived memory cells. GC B cells show lower BCR-induced signaling when compared with naive B cells, but the functional relevance is not clear. CD22 is a member of the Siglec family and functions as an inhibitory coreceptor on B cells. Interestingly, GC B cells downregulate sialic acid forms that serve as high-affinity ligands for CD22, indicating a role for CD22 ligand binding during GC responses. We studied the role of CD22 in the GC with mixed bone marrow chimeric mice and found a disadvantage of CD22-/- GC B cells during the GC reaction. Mechanistic investigations ruled out defects in dark zone/light zone distribution and affinity maturation. Rather, an increased rate of apoptosis in CD22-/- GC B cells was responsible for the disadvantage, also leading to a lower GC output in plasma cells and memory B cells. CD22-/- GC B cells showed a clearly increased calcium response upon BCR stimulation, which was almost absent in wild-type GC B cells. We conclude that the differential expression of the low-affinity cis CD22 ligands in the GC normally results in a strong attenuation of BCR signaling in GC B cells, probably due to higher CD22-BCR interactions. Therefore, attenuation of BCR signaling by CD22 is involved in GC output and B cell fate.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Memória Imunológica/imunologia , Plasmócitos/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Transdução de Sinais/imunologia , Animais , Apoptose/imunologia , Ligantes , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ácido N-Acetilneuramínico/imunologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/imunologia
17.
Nature ; 596(7870): 109-113, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34182569

RESUMO

SARS-CoV-2 mRNA-based vaccines are about 95% effective in preventing COVID-191-5. The dynamics of antibody-secreting plasmablasts and germinal centre B cells induced by these vaccines in humans remain unclear. Here we examined antigen-specific B cell responses in peripheral blood (n = 41) and draining lymph nodes in 14 individuals who had received 2 doses of BNT162b2, an mRNA-based vaccine that encodes the full-length SARS-CoV-2 spike (S) gene1. Circulating IgG- and IgA-secreting plasmablasts that target the S protein peaked one week after the second immunization and then declined, becoming undetectable three weeks later. These plasmablast responses preceded maximal levels of serum anti-S binding and neutralizing antibodies to an early circulating SARS-CoV-2 strain as well as emerging variants, especially in individuals who had previously been infected with SARS-CoV-2 (who produced the most robust serological responses). By examining fine needle aspirates of draining axillary lymph nodes, we identified germinal centre B cells that bound S protein in all participants who were sampled after primary immunization. High frequencies of S-binding germinal centre B cells and plasmablasts were sustained in these draining lymph nodes for at least 12 weeks after the booster immunization. S-binding monoclonal antibodies derived from germinal centre B cells predominantly targeted the receptor-binding domain of the S protein, and fewer clones bound to the N-terminal domain or to epitopes shared with the S proteins of the human betacoronaviruses OC43 and HKU1. These latter cross-reactive B cell clones had higher levels of somatic hypermutation as compared to those that recognized only the SARS-CoV-2 S protein, which suggests a memory B cell origin. Our studies demonstrate that SARS-CoV-2 mRNA-based vaccination of humans induces a persistent germinal centre B cell response, which enables the generation of robust humoral immunity.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Centro Germinativo/imunologia , Plasmócitos/imunologia , Vacinas Sintéticas/imunologia , Adulto , Idoso , Animais , Anticorpos Antivirais/imunologia , COVID-19/prevenção & controle , Chlorocebus aethiops , Células Clonais/citologia , Células Clonais/imunologia , Centro Germinativo/citologia , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Plasmócitos/citologia , SARS-CoV-2/imunologia , Fatores de Tempo , Células Vero
18.
Front Immunol ; 12: 624419, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34140948

RESUMO

Integrin regulation by Rap1 is indispensable for lymphocyte recirculation. In mice having B-cell-specific Rap1a/b double knockouts (DKO), the number of B cells in lymph nodes decreased to approximately 4% of that of control mice, and B cells were present in the spleen and blood. Upon the immunization with NP-CGG, DKO mice demonstrated the defective GC formation in the spleen, and the reduced NP-specific antibody production. In vitro, Rap1 deficiency impaired the movement of activated B cells along the gradients of chemoattractants known to be critical for their localization in the follicles. Furthermore, B-1a cells were almost completely absent in the peritoneal cavity, spleen and blood of adult DKO mice, and the number of B-cell progenitor/precursor (B-p) were reduced in neonatal and fetal livers. However, DKO B-ps normally proliferated, and differentiated into IgM+ cells in the presence of IL-7. CXCL12-dependent migration of B-ps on the VCAM-1 was severely impaired by Rap1 deficiency. Immunostaining study of fetal livers revealed defects in the co-localization of DKO B-ps and IL-7-producing stromal cells. This study proposes that the profound effects of Rap1-deficiency on humoral responses and B-1a cell generation may be due to or in part caused by impairments of the chemoattractant-dependent positioning and the contact with stromal cells.


Assuntos
Linfócitos B/metabolismo , Quimiotaxia de Leucócito , Centro Germinativo/metabolismo , Proteínas rap de Ligação ao GTP/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismo , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Quimiocina CXCL12/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Centro Germinativo/citologia , Centro Germinativo/efeitos dos fármacos , Centro Germinativo/imunologia , Imunidade Humoral , Imunização , Molécula 1 de Adesão Intercelular/metabolismo , Fígado/imunologia , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Precursoras de Linfócitos B/imunologia , Células Precursoras de Linfócitos B/metabolismo , Baço/imunologia , Baço/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , gama-Globulinas/farmacologia , Proteínas rap de Ligação ao GTP/genética , Proteínas rap1 de Ligação ao GTP/genética
19.
Ann Allergy Asthma Immunol ; 127(3): 301-305, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34102303

RESUMO

OBJECTIVE: To review the literature and discuss a hypothesis as to why most people do not have allergy. This hypothesis is dependent on the following 3 main components: (1) airborne allergens (eg, from pollen or mites) are weak antigens that induce a B-cell response only in immunologically most reactive subjects (ie, with atopy); (2) a roadblock to production of immunoglobulin E (IgE) is the T helper 2/interleukin 4 requirement for class switch to IgE; (3) activated germinal centers prevent the formation of mature IgE-switched B-cells, creating a second roadblock to IgE production. DATA SOURCES: Transgenic reporter mice and a cross-sectional human cohort. STUDY SELECTIONS: From the mouse studies, we selected the data on histology and tissue-derived cell suspensions published by several groups in 2011 to 2014. From the human cohort, we selected our published microarray data on the levels of allergen-specific IgE and IgG in serum. RESULTS: The immune response to airborne atopic allergens entails both IgE and IgG antibodies rather than just an IgG or IgE response. However, as expected for an immune response without mature germinal centers, the specific IgG levels will be very low, typically in the ng/ml range. CONCLUSION: Control of IgE production is not just through the T helper 2/interleukin 4-mediated class switch. Recent studies suggest that mature germinal centers are likely to provide protection against the development of allergy to airborne allergens, as well. This may explain why allergen exposure does not induce allergen-specific IgE in everyone.


Assuntos
Centro Germinativo/imunologia , Hipersensibilidade/imunologia , Animais , Antígenos/imunologia , Linfócitos B/imunologia , Humanos , Imunoglobulina E/imunologia
20.
Front Immunol ; 12: 657894, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135891

RESUMO

We aimed to investigate the mechanisms of humoral immune activation in ABMR using a MHC-mismatched rat kidney transplant model. We applied low dose cyclosporine A (loCNI) to allow donor-specific antibody (DSA) formation and rejection and high dose cyclosporine A (hiCNI) for non-rejection. DSA and leukocyte subsets were measured by flow cytometry. Germinal centers (GC), T follicular helper cells (Tfh), plasma cells and interleukin-21 (IL-21) expression were analyzed by immunofluorescence microscopy. Expression of important costimulatory molecules and cytokines was measured by qRT-PCR. Allograft rejection was evaluated by a nephropathologist. We found that DSA formation correlated with GC frequency and expansion, and that GC size was linked to the number of activated Tfh. In hiCNI, GC and activated Tfh were virtually absent, resulting in fewer plasma cells and no DSA or ABMR. Expression of B cell activating T cell cytokine IL-21 was substantially inhibited in hiCNI, but not in loCNI. In addition, hiCNI showed lower expression of ICOS ligand and IL-6, which stimulate Tfh differentiation and maintenance. Overall, Tfh:B cell crosstalk was controlled only by hiCNI treatment, preventing the development of DSA and ABMR. Additional strategies targeting Tfh:B cell interactions are needed for preventing alloantibody formation and ABMR.


Assuntos
Linfócitos B/imunologia , Comunicação Celular , Rejeição de Enxerto/imunologia , Isoanticorpos/imunologia , Transplante de Rim/efeitos adversos , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Linfócitos B/metabolismo , Biomarcadores , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/farmacologia , Comunicação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Citocinas/metabolismo , Fibrose , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Rejeição de Enxerto/metabolismo , Imunidade Humoral , Imuno-Histoquímica , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Modelos Animais , Ratos , Linfócitos T Auxiliares-Indutores/metabolismo
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