Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
1.
Immunity ; 46(4): 675-689, 2017 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-28423341

RESUMO

Activated T cells produce reactive oxygen species (ROS), which trigger the antioxidative glutathione (GSH) response necessary to buffer rising ROS and prevent cellular damage. We report that GSH is essential for T cell effector functions through its regulation of metabolic activity. Conditional gene targeting of the catalytic subunit of glutamate cysteine ligase (Gclc) blocked GSH production specifically in murine T cells. Gclc-deficient T cells initially underwent normal activation but could not meet their increased energy and biosynthetic requirements. GSH deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of NFAT and Myc transcription factors, abrogating the energy utilization and Myc-dependent metabolic reprogramming that allows activated T cells to switch to glycolysis and glutaminolysis. In vivo, T-cell-specific ablation of murine Gclc prevented autoimmune disease but blocked antiviral defense. The antioxidative GSH pathway thus plays an unexpected role in metabolic integration and reprogramming during inflammatory T cell responses.


Assuntos
Glutamato-Cisteína Ligase/deficiência , Glutationa/metabolismo , Inflamação/metabolismo , Linfócitos T/metabolismo , Animais , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Metabolismo Energético/genética , Glutamato-Cisteína Ligase/genética , Glutamina/metabolismo , Glicólise , Immunoblotting , Inflamação/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição NFATC/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo
2.
J Allergy Clin Immunol ; 153(4): 894-903, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37952833

RESUMO

The immune system protects the host from infection and works to heal damaged tissue after infection or injury. There is increasing evidence that the immune system and the nervous system work in concert to achieve these goals. The sensory nervous system senses injury, infection, and inflammation, which results in a direct pain signal. Direct activation of peripheral sensory nerves can drive an inflammatory response in the skin. Immune cells express receptors for numerous transmitters released from sensory and autonomic nerves, which allows the nervous system to communicate directly with the immune system. This communication is bidirectional because immune cells can also produce neurotransmitters. Both innate and adaptive immune cells respond to neuronal signaling, but T cells appear to be at the helm of neuroimmune communication.


Assuntos
Neuroimunomodulação , Linfócitos T , Humanos , Pele , Inflamação , Transdução de Sinais
3.
J Infect Dis ; 228(7): 966-974, 2023 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-37163747

RESUMO

Lymph nodes and spleens are innervated by sympathetic nerve fibers that enter alongside arteries. Despite discovery of these nerve fibers nearly 40 years ago, the role of these nerves during response to infection remains poorly defined. We have found that chemical depletion of sympathetic nerve fibers compromises the ability of mice to develop protective immune memory to a Staphylococcus aureus infection. Innate control of the primary infection was not impacted by sympathectomy. Germinal center formation is also compromised in nerve-depleted animals; however, protective antibody responses are still generated. Interestingly, protective CD4+ T-cell memory fails to form in the absence of sympathetic nerves after S aureus infection.


Assuntos
Infecções Estafilocócicas , Staphylococcus aureus , Camundongos , Animais , Linfócitos T CD4-Positivos , Linfonodos , Sistema Nervoso Simpático
7.
J Immunol ; 196(5): 2153-66, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26826252

RESUMO

The activation of naive CD8 T cells typically results in the formation of effector cells (TE) as well as phenotypically distinct memory cells that are retained over time. Memory CD8 T cells can be further subdivided into central memory, effector memory (TEM), and tissue-resident memory (TRM) subsets, which cooperate to confer immunological protection. Using mixed bone marrow chimeras and adoptive transfer studies in which CD8 T cells either do or do not express IL-21R, we discovered that under homeostatic or lymphopenic conditions IL-21 acts directly on CD8 T cells to favor the accumulation of TE/TEM populations. The inability to perceive IL-21 signals under competitive conditions also resulted in lower levels of TRM phenotype cells and reduced expression of granzyme B in the small intestine. IL-21 differentially promoted the expression of the chemokine receptor CX3CR1 and the integrin α4ß7 on CD8 T cells primed in vitro and on circulating CD8 T cells in the mixed bone marrow chimeras. The requirement for IL-21 to establish CD8 TE/TEM and TRM subsets was overcome by acute lymphocytic choriomeningitis virus infection; nevertheless, memory virus-specific CD8 T cells remained dependent on IL-21 for optimal accumulation in lymphopenic environments. Overall, this study reveals a context-dependent role for IL-21 in sustaining effector phenotype CD8 T cells and influencing their migratory properties, accumulation, and functions.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Movimento Celular , Memória Imunológica/imunologia , Interleucinas/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/citologia , Citometria de Fluxo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Subpopulações de Linfócitos T/citologia
8.
Proc Natl Acad Sci U S A ; 110(4): 1416-21, 2013 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-23297203

RESUMO

CD8 T-cell responses are critical for protection against intracellular pathogens and tumors. The induction and properties of these responses are governed by a series of integrated processes that rely heavily on cell-cell interactions. Intercellular adhesion molecule (ICAM)-1 functions to enhance the strength of antigenic stimulation, extend the duration of contact with antigen-presenting cells, and augment cytokine signals, which are all factors that influence peripheral CD8 T-cell differentiation. Although previous studies suggest that ICAM-1 is essential for establishing memory T-cell populations following peptide immunization, the roles of ICAM-1 in antiviral cellular immunity are less well understood. Here we show that, following a prototypic acute viral infection, the formation and maintenance of memory-phenotype CD127(hi), KLRG-1(lo) CD8 T cells does not require ICAM-1. Nevertheless, ICAM-1 expression on nonlymphocytes dictates the phenotypic and functional attributes of the antiviral CD8 T-cell populations that develop and promotes the gradual attrition of residual effector-like CD127(lo), KLRG-1(hi) CD8 T cells during the memory phase of the response. Although memory T cells do emerge and are maintained if ICAM-1 expression is abolished, the secondary proliferative capacity of these T cells is severely curtailed. Collectively, these studies reveal potential dual roles for ICAM-1 in both promoting the decay of effector responses and programming the sensitivity of memory CD8 T cells to secondary stimuli.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Memória Imunológica/fisiologia , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Doença Aguda , Animais , Molécula 1 de Adesão Intercelular/genética , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Lectinas Tipo C , Ativação Linfocitária , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Imunológicos/metabolismo
9.
Trends Immunol ; 32(4): 180-6, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21371940

RESUMO

The activation and differentiation of CD8 T cells is a necessary first step that endows these cells with the phenotypic and functional properties required for the control of intracellular pathogens. The induction of the CD8 T cell responses typically results in the development of a massive overall population of effector cells, comprising both highly functional but short-lived terminally differentiated cells, as well as a smaller subset of precursors that are predisposed to survive and transition into the memory T cell pool. In this review, we discuss how inflammatory cytokines and IL-2 bias the initial response towards short-lived effector generation, and also highlight the potential counterbalancing role of IL-21.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Interleucina-2/imunologia , Interleucinas/imunologia , Animais , Imunidade Inata , Memória Imunológica , Inflamação/imunologia
10.
Trends Neurosci ; 47(3): 165-166, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38129194

RESUMO

Stress contributes to infection and cancer susceptibility, but the mediating mechanisms are still being elucidated. CD8 T cells are critical players in antiviral and antitumor immune responses. A recent study by Globig et al., together with a growing body of literature, link norepinephrine produced during the stress response to CD8 T cell dysfunction.


Assuntos
Adrenérgicos , Neoplasias , Humanos , Infecção Persistente , Ativação Linfocitária , Linfócitos T CD8-Positivos/patologia
11.
Cell Rep ; 43(5): 114245, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38761377

RESUMO

Recurrent Clostridioides difficile infection (CDI) results in significant morbidity and mortality. We previously established that CDI in mice does not protect against reinfection and is associated with poor pathogen-specific B cell memory (Bmem), recapitulating our observations with human Bmem. Here, we demonstrate that the secreted toxin TcdB2 is responsible for subversion of Bmem responses. TcdB2 from an endemic C. difficile strain delayed immunoglobulin G (IgG) class switch following vaccination, attenuated IgG recall to a vaccine booster, and prevented germinal center formation. The mechanism of TcdB2 action included increased B cell CXCR4 expression and responsiveness to its ligand CXCL12, accounting for altered cell migration and a failure of germinal center-dependent Bmem. These results were reproduced in a C. difficile infection model, and a US Food and Drug Administration (FDA)-approved CXCR4-blocking drug rescued germinal center formation. We therefore provide mechanistic insights into C. difficile-associated pathogenesis and illuminate a target for clinical intervention to limit recurrent disease.


Assuntos
Proteínas de Bactérias , Toxinas Bacterianas , Clostridioides difficile , Centro Germinativo , Receptores CXCR4 , Animais , Camundongos , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/imunologia , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/metabolismo , Quimiocina CXCL12/metabolismo , Clostridioides difficile/imunologia , Clostridioides difficile/patogenicidade , Infecções por Clostridium/imunologia , Infecções por Clostridium/microbiologia , Centro Germinativo/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Memória Imunológica , Camundongos Endogâmicos C57BL , Receptores CXCR4/metabolismo , Receptores CXCR4/imunologia
12.
Nat Cancer ; 4(10): 1437-1454, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37640929

RESUMO

Cholinergic nerves are involved in tumor progression and dissemination. In contrast to other visceral tissues, cholinergic innervation in the hepatic parenchyma is poorly detected. It remains unclear whether there is any form of cholinergic regulation of liver cancer. Here, we show that cholinergic T cells curtail the development of liver cancer by supporting antitumor immune responses. In a mouse multihit model of hepatocellular carcinoma (HCC), we observed activation of the adaptive immune response and induction of two populations of CD4+ T cells expressing choline acetyltransferase (ChAT), including regulatory T cells and dysfunctional PD-1+ T cells. Tumor antigens drove the clonal expansion of these cholinergic T cells in HCC. Genetic ablation of Chat in T cells led to an increased prevalence of preneoplastic cells and exacerbated liver cancer due to compromised antitumor immunity. Mechanistically, the cholinergic activity intrinsic in T cells constrained Ca2+-NFAT signaling induced by T cell antigen receptor engagement. Without this cholinergic modulation, hyperactivated CD25+ T regulatory cells and dysregulated PD-1+ T cells impaired HCC immunosurveillance. Our results unveil a previously unappreciated role for cholinergic T cells in liver cancer immunobiology.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Receptor de Morte Celular Programada 1/genética , Monitorização Imunológica , Linfócitos T Reguladores/patologia
13.
J Immunol ; 185(6): 3643-51, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20720198

RESUMO

During many chronic infections, the responding CD8 T cells become exhausted as they progressively lose their ability to elaborate key effector functions. Unlike prototypic memory CD8 cells, which rapidly synthesize IFN-gamma following activation, severely exhausted T cells fail to produce this effector molecule. Nevertheless, the ontogeny of exhausted CD8 T cells, as well as the underlying mechanisms that account for their functional inactivation, remains ill defined. We have used cytokine reporter mice, which mark the transcription of IFN-gamma mRNA by the expression of Thy1.1, to decipher how activation events during the early stages of a chronic infection dictate the development of exhaustion. We show that virus-specific CD8 T cells clearly respond during the early stages of chronic lymphocytic choriomeningitis virus infection, and that this early T cell response is more pronounced than that initially observed in acutely infected hosts. Thus, exhausted CD8 T cells appear to emerge from populations of potently activated precursors. Unlike acute infections, which result in massive expansion of the responding T cells, there is a rapid attenuation of further expansion during chronic infections. The exhausted T cells that subsequently emerge in chronically infected hosts are incapable of producing the IFN-gamma protein. Surprisingly, high levels of the IFN-gamma transcript are still present in exhausted cells, demonstrating that ablation of IFN-gamma production by exhausted cells is not due to transcriptional silencing. Thus, posttranscription regulatory mechanisms likely disable this effector module.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Inativação Gênica/imunologia , Interferon gama/genética , Interferon gama/metabolismo , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Transcrição Gênica/imunologia , Doença Aguda , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/patologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Doença Crônica , Técnicas de Introdução de Genes , Genes Reporter/imunologia , Interferon gama/biossíntese , Ativação Linfocitária/genética , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Coriomeningite Linfocítica/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células-Tronco/imunologia , Células-Tronco/patologia , Células-Tronco/virologia , Antígenos Thy-1/biossíntese , Antígenos Thy-1/genética , Regulação para Cima/genética , Regulação para Cima/imunologia , Ativação Viral/imunologia
14.
Immunology ; 129(4): 474-81, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20201977

RESUMO

T-cell exhaustion is characterized by the stepwise and progressive loss of T-cell functions and can culminate in the physical deletion of the responding cells. Exhaustion is well-defined during chronic lymphocytic choriomeningitis virus infection and commonly develops under conditions of antigen-persistence, which occur following many chronic infections that are of significant public health concern including hepatitis B virus, hepatitis C virus and human immunodeficiency virus infections, as well as during tumour outgrowth. Exhaustion is not a uniformly disabled setting as a gradation of phenotypic and functional defects can manifest, and these cells are distinct from prototypic effector, memory and also anergic T cells. We are gaining insights into the extrinsic and intrinsic factors that determine the severity of exhaustion. These include the duration and magnitude of antigenic activation, availability of CD4 T-cell help, the levels of stimulatory and suppressive cytokines, as well as the expression of activatory and inhibitory receptors. More information is now becoming available regarding the molecular mechanisms that attenuate the responsiveness of exhausted T cells. As the parameters that dictate exhaustion are more thoroughly defined, this is fostering the development of methods that prevent and rejuvenate functionally inferior responses. In this article we discuss our current understanding of the properties of exhausted T cells and the mechanisms that promote and maintain this state.


Assuntos
Linfócitos T/imunologia , Animais , Citocinas/imunologia , Humanos , Linfócitos T/virologia
15.
J Biomed Biotechnol ; 2010: 159152, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20379363

RESUMO

CD8 T cells play a vital role in the immunological protection against intracellular pathogens. Ideally, robust effector responses are induced, which eradicate the pathogen, and durable memory CD8 T cells are also established, which help confer protection against subsequent reinfection. The quality and magnitude of these responses is dictated by multiple factors, including their initial interactions with professional antigen-presenting cells, as well as the cytokine milieu and availability of CD4 T cell help. These factors set the transcriptional landscape of the responding T cells, which in turn influences their phenotypic and functional attributes as well as ultimate fate. Under certain conditions, such as during chronic infections, the development of these usually successful responses becomes subverted. Here we discuss advances in our understanding of the cellular and molecular determinants of T cell quality, and the formation of effector, memory, and exhausted CD8 T cells, during acute and chronic infections.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções/imunologia , Doença Aguda , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Doença Crônica , Apresentação Cruzada/imunologia , Humanos , Memória Imunológica/imunologia , Transcrição Gênica/imunologia
16.
J Immunol ; 181(5): 3077-88, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18713978

RESUMO

Apoptosis plays an important role in eliminating UV-damaged keratinocytes, but its role in UV-induced immune suppression is not clear. Langerhans cells (LCs) may function as inducers of immune suppression. We have shown that LCs derived from mice deficient in the proapoptotic Bid (BH3-interacting death domain protein) gene (Bid KO) resist apoptosis and induce amplified immune responses. In this report, we examined responses in Bid KO mice to UVB exposure. Acute UV exposure led Bid KO mice to develop fewer apoptotic cells and retain a greater fraction of LCs in the epidermal layer of skin in comparison to wild-type mice. Bid KO mice were also markedly resistant to local and systemic UV tolerance induction to hapten sensitization and contact hypersensitivity responses. Elicitation responses and inflammation at skin sensitization sites in UV-treated Bid KO mice were equal to or greater than nonsuppressed control responses. In Bid KO mice, LCs accumulated in lymph nodes to greater numbers, demonstrated longer lifespans, and contained fewer DNA-damaged cells. These studies provide evidence that Bid activation is a critical upstream mediator in UV-induced keratinocyte and LC apoptosis and that its absence abrogates UV-induced immune tolerance.


Assuntos
Apoptose/efeitos da radiação , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/fisiologia , Terapia de Imunossupressão , Pele/citologia , Raios Ultravioleta , Animais , Proteínas Reguladoras de Apoptose , Tolerância Imunológica/efeitos da radiação , Queratinócitos/citologia , Células de Langerhans/citologia , Camundongos , Camundongos Knockout , Pele/efeitos da radiação
17.
Nat Commun ; 10(1): 2678, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213601

RESUMO

Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within the tumor microenvironment (TME) is unclear. We demonstrate that Fcmr (Toso), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer. In a syngeneic melanoma model, Fcmr ablation in myeloid cells suppressed tumor growth and extended mouse survival. Fcmr deficiency increased myeloid cell population density in this malignancy and enhanced anti-tumor immunity. Single-cell RNA sequencing of Fcmr-deficient tumor-associated mononuclear phagocytes revealed a unique subset with enhanced antigen processing/presenting properties. Conversely, Fcmr activity negatively regulated the activation and migratory capacity of myeloid cells in vivo, and T cell activation by bone marrow-derived dendritic cells in vitro. Therapeutic targeting of Fcmr during oncogenesis decreased tumor growth when used as a single agent or in combination with anti-PD-1. Thus, Fcmr regulates myeloid cell activation within the TME and may be a potential therapeutic target.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Transporte/metabolismo , Melanoma Experimental/imunologia , Proteínas de Membrana/metabolismo , Monócitos/imunologia , Neoplasias Cutâneas/imunologia , Animais , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Linhagem Celular Tumoral/transplante , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Feminino , Ativação Linfocitária/imunologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/mortalidade , Melanoma Experimental/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
19.
Science ; 363(6427): 639-644, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30733420

RESUMO

Although widely studied as a neurotransmitter, T cell-derived acetylcholine (ACh) has recently been reported to play an important role in regulating immunity. However, the role of lymphocyte-derived ACh in viral infection is unknown. Here, we show that the enzyme choline acetyltransferase (ChAT), which catalyzes the rate-limiting step of ACh production, is robustly induced in both CD4+ and CD8+ T cells during lymphocytic choriomeningitis virus (LCMV) infection in an IL-21-dependent manner. Deletion of Chat within the T cell compartment in mice ablated vasodilation in response to infection, impaired the migration of antiviral T cells into infected tissues, and ultimately compromised the control of chronic LCMV clone 13 infection. Our results reveal a genetic proof of function for ChAT in T cells during viral infection and identify a pathway of T cell migration that sustains antiviral immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Colina O-Acetiltransferase/imunologia , Interleucinas/imunologia , Coriomeningite Linfocítica/imunologia , Animais , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/enzimologia , Movimento Celular , Colina O-Acetiltransferase/genética , Feminino , Ativação Linfocitária , Vírus da Coriomeningite Linfocítica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vasodilatação
20.
Front Immunol ; 9: 638, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29755449

RESUMO

The immune and nervous systems are two major organ systems responsible for host defense and memory. Both systems achieve memory and learning that can be retained, retrieved, and utilized for decades. Here, we report the surprising discovery that peripheral sensory neurons of the dorsal root ganglia (DRGs) of immunized mice contain antigen-specific antibodies. Using a combination of rigorous molecular genetic analyses, transgenic mice, and adoptive transfer experiments, we demonstrate that DRGs do not synthesize these antigen-specific antibodies, but rather sequester primarily IgG1 subtype antibodies. As revealed by RNA-seq and targeted quantitative PCR (qPCR), dorsal root ganglion (DRG) sensory neurons harvested from either naïve or immunized mice lack enzymes (i.e., RAG1, RAG2, AID, or UNG) required for generating antibody diversity and, therefore, cannot make antibodies. Additionally, transgenic mice that express a reporter fluorescent protein under the control of Igγ1 constant region fail to express Ighg1 transcripts in DRG sensory neurons. Furthermore, neural sequestration of antibodies occurs in mice rendered deficient in neuronal Rag2, but antibody sequestration is not observed in DRG sensory neurons isolated from mice that lack mature B cells [e.g., Rag1 knock out (KO) or µMT mice]. Finally, adoptive transfer of Rag1-deficient bone marrow (BM) into wild-type (WT) mice or WT BM into Rag1 KO mice revealed that antibody sequestration was observed in DRG sensory neurons of chimeric mice with WT BM but not with Rag1-deficient BM. Together, these results indicate that DRG sensory neurons sequester and retain antigen-specific antibodies released by antibody-secreting plasma cells. Coupling this work with previous studies implicating DRG sensory neurons in regulating antigen trafficking during immunization raises the interesting possibility that the nervous system collaborates with the immune system to regulate antigen-mediated responses.


Assuntos
Anticorpos/metabolismo , Linfócitos B/imunologia , Gânglios Espinais/patologia , Inflamação/imunologia , Células Receptoras Sensoriais/metabolismo , Animais , Antígenos/imunologia , Células Cultivadas , Imunidade Humoral , Imunização , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroimunomodulação , Células Receptoras Sensoriais/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA