RESUMO
Seasonal influenza vaccination elicits hemagglutinin (HA)-specific memory B (Bmem) cells, and although multiple Bmem cell populations have been characterized, considerable heterogeneity exists. We found that HA-specific human Bmem cells differed in the expression of surface marker FcRL5 and transcriptional factor T-bet. FcRL5+T-bet+ Bmem cells were transcriptionally similar to effector-like memory cells, while T-betnegFcRL5neg Bmem cells exhibited stem-like central memory properties. FcRL5+ Bmem cells did not express plasma-cell-commitment factors but did express transcriptional, epigenetic, metabolic, and functional programs that poised these cells for antibody production. Accordingly, HA+ T-bet+ Bmem cells at day 7 post-vaccination expressed intracellular immunoglobulin, and tonsil-derived FcRL5+ Bmem cells differentiated more rapidly into antibody-secreting cells (ASCs) in vitro. The T-bet+ Bmem cell response positively correlated with long-lived humoral immunity, and clonotypes from T-bet+ Bmem cells were represented in the secondary ASC response to repeat vaccination, suggesting that this effector-like population predicts influenza vaccine durability and recall potential.
Assuntos
Vacinas contra Influenza , Influenza Humana , Humanos , Influenza Humana/prevenção & controle , Formação de Anticorpos , Células B de Memória , Vacinação , Memória Imunológica , Anticorpos AntiviraisRESUMO
Memory B cells are found in lymphoid and non-lymphoid tissues, suggesting that some may be tissue-resident cells. Here we show that pulmonary influenza infection elicited lung-resident memory B cells (BRM cells) that were phenotypically and functionally distinct from their systemic counterparts. BRM cells were established in the lung early after infection, in part because their placement required local antigen encounter. Lung BRM cells, but not systemic memory B cells, contributed to early plasmablast responses following challenge infection. Following secondary infection, antigen-specific BRM cells differentiated in situ, whereas antigen-non-specific BRM cells were maintained as memory cells. These data demonstrate that BRM cells are an important component of immunity to respiratory viruses such as influenza virus and suggest that vaccines designed to elicit BRM cells must deliver antigen to the lungs.
Assuntos
Antígenos Virais/imunologia , Linfócitos B/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Pulmão/imunologia , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/fisiologia , Plasmócitos/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Feminino , Humanos , Imunidade Humoral , Memória Imunológica , Pulmão/virologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Interleukin (IL)-22 is central to immune defense at barrier sites. We examined the contributions of innate lymphoid cell (ILC) and T cell-derived IL-22 during Citrobacter rodentium (C.r) infection using mice that both report Il22 expression and allow lineage-specific deletion. ILC-derived IL-22 activated STAT3 in C.r-colonized surface intestinal epithelial cells (IECs) but only temporally restrained bacterial growth. T cell-derived IL-22 induced a more robust and extensive activation of STAT3 in IECs, including IECs lining colonic crypts, and T cell-specific deficiency of IL-22 led to pathogen invasion of the crypts and increased mortality. This reflected a requirement for T cell-derived IL-22 for the expression of a host-protective transcriptomic program that included AMPs, neutrophil-recruiting chemokines, and mucin-related molecules, and it restricted IFNγ-induced proinflammatory genes. Our findings demonstrate spatiotemporal differences in the production and action of IL-22 by ILCs and T cells during infection and reveal an indispensable role for IL-22-producing T cells in the protection of the intestinal crypts.
Assuntos
Citrobacter rodentium , Infecções por Enterobacteriaceae , Animais , Antibacterianos , Imunidade Inata , Interleucinas/metabolismo , Mucosa Intestinal , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/metabolismo , Interleucina 22RESUMO
Interleukin 2 (IL-2) promotes Foxp3+ regulatory T (Treg) cell responses, but inhibits T follicular helper (TFH) cell development. However, it is not clear how IL-2 affects T follicular regulatory (TFR) cells, a cell type with properties of both Treg and TFH cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented TFR cell development by a Blimp-1-dependent mechanism. However, once the immune response resolved, some Treg cells downregulated CD25, upregulated Bcl-6 and differentiated into TFR cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones. Thus, unlike its effects on conventional Treg cells, IL-2 inhibits TFR cell responses.
Assuntos
Interleucina-2/farmacologia , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Movimento Celular/genética , Movimento Celular/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica/métodos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Interleucina-2/administração & dosagem , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Orthomyxoviridae/fisiologia , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismoRESUMO
Although viral infections elicit robust interferon-γ (IFN-γ) and long-lived antibody-secreting cell (ASC) responses, the roles for IFN-γ and IFN-γ-induced transcription factors (TFs) in ASC development are unclear. We showed that B cell intrinsic expression of IFN-γR and the IFN-γ-induced TF T-bet were required for T-helper 1 cell-induced differentiation of B cells into ASCs. IFN-γR signaling induced Blimp1 expression in B cells but also initiated an inflammatory gene program that, if not restrained, prevented ASC formation. T-bet did not affect Blimp1 upregulation in IFN-γ-activated B cells but instead regulated chromatin accessibility within the Ifng and Ifngr2 loci and repressed the IFN-γ-induced inflammatory gene program. Consistent with this, B cell intrinsic T-bet was required for formation of long-lived ASCs and secondary ASCs following viral, but not nematode, infection. Therefore, T-bet facilitates differentiation of IFN-γ-activated inflammatory effector B cells into ASCs in the setting of IFN-γ-, but not IL-4-, induced inflammatory responses.
Assuntos
Linfócitos B/imunologia , Interferon gama/imunologia , Receptores de Interferon/metabolismo , Proteínas com Domínio T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Células Produtoras de Anticorpos/imunologia , Linfócitos B/citologia , Diferenciação Celular/imunologia , Células Cultivadas , Cromatina/metabolismo , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nematospiroides dubius/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/biossíntese , Infecções por Strongylida/imunologia , Infecções por Strongylida/parasitologia , Proteínas com Domínio T/genética , Receptor de Interferon gamaRESUMO
Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5- CD11c+ cells (DN2) representing pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets.
Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptor 7 Toll-Like/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Feminino , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/imunologia , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Plasmócitos/metabolismo , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia , Adulto JovemRESUMO
Following the fate of antigen-specific memory B cells has been difficult. In this issue of Immunity, Krishnamurty et al. (2016) use a novel B cell tetramer to define Plasmodium-specific memory B cells in parasite-infected mice and demonstrate that after re-infection, somatically mutated IgM(+) memory B cells function as first responders by rapidly differentiating into T-cell-dependent plasmablasts and T-cell-independent plasma cells.
Assuntos
Memória Imunológica/imunologia , Malária/imunologia , Animais , Linfócitos B/imunologia , Imunoglobulina M , Camundongos , Linfócitos T/imunologiaRESUMO
Exposure to environmental antigens, such as house dust mite (HDM), often leads to T helper 2 (Th2) cell-driven allergic responses. However, the mechanisms underlying the development of these responses are incompletely understood. We found that the initial exposure to HDM did not lead to Th2 cell development but instead promoted the formation of interleukin-4 (IL-4)-committed T follicular helper (Tfh) cells. Following challenge exposure to HDM, Tfh cells differentiated into IL-4 and IL-13 double-producing Th2 cells that accumulated in the lung and recruited eosinophils. B cells were required to expand IL-4-committed Tfh cells during the sensitization phase, but did not directly contribute to disease. Impairment of Tfh cell responses during the sensitization phase or Tfh cell depletion prevented Th2 cell-mediated responses following challenge. Thus, our data demonstrate that Tfh cells are precursors of HDM-specific Th2 cells and reveal an unexpected role of B cells and Tfh cells in the pathogenesis of allergic asthma.
Assuntos
Asma/imunologia , Linfócitos B/imunologia , Hipersensibilidade/imunologia , Células Th2/imunologia , Animais , Antígenos de Dermatophagoides/administração & dosagem , Antígenos de Dermatophagoides/imunologia , Asma/etiologia , Diferenciação Celular , Células Cultivadas , Humanos , Hipersensibilidade/complicações , Imunidade , Inalação , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Depleção Linfocítica , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , PyroglyphidaeRESUMO
Long-lived T-dependent B cell responses fail to develop during persistent infection of mice with Borrelia burgdorferi, the causative agent of Lyme disease, raising questions about the induction and/or functionality of anti-B. burgdorferi adaptive immune responses. Yet, a lack of reagents has limited investigations into B. burgdorferi-specific T and B cells. We attempted two approaches to track B. burgdorferi-induced CD4 T cells. First, a B. burgdorferi mutant was generated with an influenza hemagglutinin (HA) peptide, HA111-119, inserted into the B. burgdorferi arthritis-related protein (Arp) locus. Although this B. burgdorferi arp::HA strain remained infectious, peptide-specific TCR transgenic CD4 T cells in vitro, or adoptively transferred into B. burgdorferi arp::HA-infected BALB/c mice, did not clonally expand above those of recipients infected with the parental B. burgdorferi strain or a B. burgdorferi mutant containing an irrelevant peptide. Some expansion, however, occurred in B. burgdorferi arp::HA-infected BALB/c SCID mice. Second, a (to our knowledge) newly identified I-Ab-restricted CD4 T cell epitope, Arp152-166, was used to generate Arp MHC class II tetramers. Flow cytometry showed small numbers of Arp-specific CD4 T cells emerging in mice infected with B. burgdorferi but not with Arp-deficient Borrelia afzelii. Although up to 30% of Arp-specific CD4 T cells were ICOS+PD-1+CXCR5+BCL6+ T follicular helper cells, their numbers declined after day 12, before germinal centers (GCs) are prominent. Although some Arp-specific B cells, identified using fluorochrome-labeled rArp proteins, had the phenotype of GC B cells, their frequencies did not correlate with anti-Arp serum IgG. The data suggest a failure not in the induction, but in the maintenance of GC T follicular helper and/or B cells to B. burgdorferi.
Assuntos
Borrelia burgdorferi , Doença de Lyme , Camundongos , Animais , Linfócitos T CD4-Positivos , Camundongos SCID , Linfócitos BRESUMO
Although cognate encounters between antigen-bearing dendritic cells (DCs) that express the chemokine receptor CCR7 and CCR7(+) naive T cells take place in the T cell zone of lymph nodes, it is unknown whether the colocalization of DCs and T cells in the T cell area is required for the generation of effector cells. Here we found that after infection with an intestinal nematode, antigen-bearing DCs and CD4(+) T cells upregulated the chemokine receptor CXCR5 and localized together outside the T cell zone by a mechanism dependent on the chemokine CXCL13, B cells and lymphotoxin. Notably, lymphotoxin-expressing B cells, CXCR5-expressing DCs and T cells, and CXCL13 were also necessary for development of interleukin 4 (IL-4)-producing type 2 helper T cells (T(H)2 cells), which suggests that T(H)2 differentiation can initiate outside the T cell zone.
Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Linfotoxina-alfa/imunologia , Receptores CXCR5/imunologia , Infecções por Strongylida/imunologia , Células Th2/imunologia , Animais , Quimiocina CXCL13/imunologia , Interleucina-4/imunologia , Ativação Linfocitária/imunologia , Linfotoxina-alfa/biossíntese , Linfotoxina-alfa/genética , Camundongos , Camundongos Endogâmicos C57BL , Nematospiroides dubius/imunologiaRESUMO
Memory CD8(+) T cells are programmed during the primary response for robust secondary responsiveness. Here we show that CD8(+) T cells responding to different epitopes of influenza virus received qualitatively different signals during the primary response that altered their secondary responsiveness. Nucleoprotein (NP)-specific CD8(+) T cells encountered antigen on CD40-licensed, CD70-expressing, CD103(-)CD11b(hi) dendritic cells (DCs) at later times in the primary response. As a consequence, they maintained CD25 expression and responded to interleukin-2 (IL-2) and CD27, which together programmed their robust secondary proliferative capacity and interferon-γ (IFN-γ)-producing ability. In contrast, polymerase (PA)-specific CD8(+) T cells did not encounter antigen-bearing, CD40-activated DCs at later times in the primary response, did not receive CD27 and CD25 signals, and were not programmed to become memory CD8(+) T cells with strong proliferative and cytokine-producing ability. As a result, CD8(+) T cells responding to abundant antigens, like NP, dominated the secondary response.
Assuntos
Apresentação de Antígeno/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Memória Imunológica/imunologia , Vírus da Influenza A/imunologia , Transferência Adotiva , Animais , Antígenos CD/imunologia , Antígeno CD11b/imunologia , Ligante CD27/biossíntese , Antígenos CD40/antagonistas & inibidores , Antígenos CD40/genética , Antígenos CD40/imunologia , Células Cultivadas , RNA Polimerases Dirigidas por DNA/imunologia , Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe I/farmacologia , Cadeias alfa de Integrinas/imunologia , Interferon gama/biossíntese , Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Subunidade alfa de Receptor de Interleucina-2/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor , Nucleoproteínas/imunologia , Infecções por Orthomyxoviridae/imunologia , Transdução de Sinais/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Proteínas do Core Viral/imunologiaRESUMO
Upon receiving cognate and co-stimulatory priming signals from antigen (Ag)-presenting dendritic cells (DCs) in secondary lymphoid tissues, naïve CD4+ T cells differentiate into distinct effector and memory populations. These alternate cell fate decisions, which ultimately control the T-cell functional attributes, are dictated by programming signals provided by Ag-bearing DCs and by other cells that are present in the microenvironment in which T-cell priming occurs. We know that DCs can be subdivided into multiple populations and that the various DC subsets exhibit differential capacities to initiate development of the different CD4+ T-helper populations. What is less well understood is why different subanatomic regions of secondary lymphoid tissues are colonized by distinct populations of Ag-presenting DCs and how the location of these DCs influences the type of T-cell response that will be generated. Here we review how chemokine receptors and their ligands, which position allergen and nematode-activated DCs within different microdomains of secondary lymphoid tissues, contribute to the establishment of IL-4 committed follicular helper T and type 2 helper cell responses.
Assuntos
Células Dendríticas/imunologia , Linfonodos/imunologia , Linfócitos T/imunologia , Animais , Apresentação de Antígeno , Comunicação Celular , Compartimento Celular , Diferenciação Celular , Linhagem da Célula , Humanos , Ativação Linfocitária , Equilíbrio Th1-Th2RESUMO
NAD, a key co-enzyme required for cell metabolism, is synthesized via two pathways in most organisms. Since schistosomes apparently lack enzymes required for de novo NAD biosynthesis, we evaluated whether these parasites, which infect >200 million people worldwide, maintain NAD homeostasis via the NAD salvage biosynthetic pathway. We found that intracellular NAD levels decline in schistosomes treated with drugs that block production of nicotinamide or nicotinamide mononucleotide-known NAD precursors in the non-deamidating salvage pathway. Moreover, in vitro inhibition of the NAD salvage pathway in schistosomes impaired egg production, disrupted the outer membranes of both immature and mature parasites and caused loss of mobility and death. Inhibiting the NAD salvage pathway in schistosome-infected mice significantly decreased NAD levels in adult parasites, which correlated with reduced egg production, fewer liver granulomas and parasite death. Thus, schistosomes, unlike their mammalian hosts, appear limited to one metabolic pathway to maintain NAD-dependent metabolic processes.
Assuntos
Interações Hospedeiro-Parasita/fisiologia , NAD/metabolismo , Schistosoma mansoni/fisiologia , Esquistossomose mansoni/metabolismo , Animais , Feminino , Camundongos , Reprodução/fisiologia , Esquistossomose mansoni/patologiaRESUMO
The question of which dendritic cells (DCs) respond to pulmonary antigens and cross-prime CD8(+) T cells remains controversial. We show here that influenza-specific CD8(+) T cell priming was controlled by different DCs at different times after infection. Whereas early priming was controlled by both CD103(+)CD11b(lo) and CD103(-)CD11b(hi) DCs, CD103(-)CD11b(hi) DCs dominated antigen presentation at the peak of infection. Moreover, CD103(-)CD11b(hi) DCs captured exogenous antigens in the lungs and directly cross-primed CD8(+) T cells in the draining lymph nodes without transferring antigen to CD8alpha(+) DCs. Finally, we show that CD103(-)CD11b(hi) DCs were the only DCs to express CD70 after influenza infection and that CD70 expression on CD103(-)CD11b(hi) DCs licensed them to expand CD8(+) T cell populations responding to both influenza and exogenous ovalbumin.
Assuntos
Ligante CD27/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Linfócitos T CD4-Positivos/virologia , Apresentação Cruzada/imunologia , Células Dendríticas/virologia , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe II/imunologia , Imunofenotipagem , Cinética , Linfonodos/imunologia , Linfonodos/virologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Nucleocapsídeo/imunologia , Infecções por Orthomyxoviridae/virologiaRESUMO
Alloimmune responses in kidney transplant (KT) patients previously hospitalized with COVID-19 are understudied. We analyzed a cohort of 112 kidney transplant recipients who were hospitalized following a positive SARS-CoV-2 test result during the first 20 months of the COVID-19 pandemic. We found a cumulative incidence of 17% for the development of new donor-specific antibodies (DSA) or increased levels of pre-existing DSA in hospitalized SARS-CoV-2-infected KT patients. This risk extended 8 months post-infection. These changes in DSA status were associated with late allograft dysfunction. Risk factors for new or increased DSA responses in this KT patient cohort included the presence of circulating DSA pre-COVID-19 diagnosis and time post-transplantation. COVID-19 vaccination prior to infection and remdesivir administration during infection were each associated with decreased likelihood of developing a new or increased DSA response. These data show that new or enhanced DSA responses frequently occur among KT patients requiring admission with COVID-19 and suggest that surveillance, vaccination, and antiviral therapies may be important tools to prevent alloimmunity in these individuals.
Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Transplante de Rim , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Anticorpos , COVID-19/prevenção & controle , Teste para COVID-19 , Vacinas contra COVID-19/uso terapêutico , Rejeição de Enxerto , Antígenos HLA , Humanos , Pandemias , SARS-CoV-2 , Transplantados , VacinaçãoRESUMO
T follicular helper (Tfh) cells promote T cell-dependent humoral immune responses by providing T cell help to B cells and by promoting germinal center (GC) formation and long-lived antibody responses. However, the cellular and molecular mechanisms that control Tfh cell differentiation in vivo are incompletely understood. Here we show that interleukin-2 (IL-2) administration impaired influenza-specific GCs, long-lived IgG responses, and Tfh cells. IL-2 did not directly inhibit GC formation, but instead suppressed the differentiation of Tfh cells, thereby hindering the maintenance of influenza-specific GC B cells. Our data demonstrate that IL-2 is a critical factor that regulates successful Tfh and B cell responses in vivo and regulates Tfh cell development.
Assuntos
Diferenciação Celular/imunologia , Centro Germinativo/imunologia , Interleucina-2/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Centro Germinativo/citologia , Centro Germinativo/metabolismo , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Orthomyxoviridae/imunologia , Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6 , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
The ectodomain of the plasma membrane ectoenzyme CD38 functions as both an NAD glycohydrolase and an ADP-ribosyl cyclase by catalyzing, respectively, the conversion of NAD to nicotinamide and ADP-ribose or cyclic ADP-ribose. CD38 is attracting particular attention in cancer therapy. An anti-CD38 monoclonal antibody (daratumumab) was approved for treatment of patients with multiple myeloma. However, the role of CD38 in non-hematological malignancies has not been explored. Previously, we reported that ADP-ribose-acceptor hydrolase (ARH)-1 deficiency in mice was associated with tumor development. In the present study, we found that in wild-type and ARH1-deficient mice deletion of the CD38 gene reduced tumor formation. Significant reductions in tumor number were observed in lymphomas, adenocarcinomas and hemangio/histolytic sarcomas. Consistent with a role for CD38 in tumorigenesis, CRISPR/Cas9-based knockout of CD38 in A549 human adenocarcinoma cells inhibited anchorage-independent cell growth, cell invasion and xenograft growth in nude mice. CD38 mRNA and protein expression were evaluated in human lung cancer cell lines and in human lung cancer specimens. CD38 overexpression in tumor cells was identified in 11 of 27 patient samples. In addition, some human lung cancer cell lines had dramatically higher CD38 mRNA and protein expression than normal cells. Consistent with these observations, search of the Oncomine database showed that some human lung adenocarcinomas had higher CD38 mRNA levels compared to normal lung tissues. In total, our data are consistent with the conclusion that CD38 plays a role in murine and human lung tumorigenesis and that anti-CD38 treatment may have therapeutic potential in lung cancer.
Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Carcinogênese/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , ADP-Ribosil Ciclase 1/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Proliferação de Células/fisiologia , Técnicas de Inativação de Genes , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos NusRESUMO
Immunity to the intestinal parasite Heligomosomoides polygyrus is dependent on the successful generation of T helper 2 (Th2) memory cells. We showed that B cells contribute to immunity against H. polygyrus by producing antibody (Ab) and by promoting expansion and differentiation of primary and memory Th2 cells. We also demonstrated that cytokine-producing effector B cells were essential for effective immunity to H. polygyrus. Tumor necrosis factor alpha production by B cells was necessary for sustained Ab production, whereas interleukin 2 production by B cells was necessary for Th2 cell expansion and differentiation. These results show that B cells mediate protection from pathogens not only by presenting antigen and secreting antibody but also by producing cytokines that regulate the quality and magnitude of humoral and cellular immune responses.