RESUMEN
Peripheral sensory neurons widely innervate various tissues to continuously monitor and respond to environmental stimuli. Whether peripheral sensory neurons innervate the spleen and modulate splenic immune response remains poorly defined. Here, we demonstrate that nociceptive sensory nerve fibers extensively innervate the spleen along blood vessels and reach B cell zones. The spleen-innervating nociceptors predominantly originate from left T8-T13 dorsal root ganglia (DRGs), promoting the splenic germinal center (GC) response and humoral immunity. Nociceptors can be activated by antigen-induced accumulation of splenic prostaglandin E2 (PGE2) and then release calcitonin gene-related peptide (CGRP), which further promotes the splenic GC response at the early stage. Mechanistically, CGRP directly acts on B cells through its receptor CALCRL-RAMP1 via the cyclic AMP (cAMP) signaling pathway. Activating nociceptors by ingesting capsaicin enhances the splenic GC response and anti-influenza immunity. Collectively, our study establishes a specific DRG-spleen sensory neural connection that promotes humoral immunity, suggesting a promising approach for improving host defense by targeting the nociceptive nervous system.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Centro Germinal , Inmunidad Humoral , Bazo , Animales , Masculino , Ratones , Linfocitos B/inmunología , Linfocitos B/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Capsaicina/farmacología , AMP Cíclico/metabolismo , Dinoprostona/metabolismo , Ganglios Espinales/metabolismo , Centro Germinal/inmunología , Ratones Endogámicos C57BL , Nociceptores/metabolismo , Proteína 1 Modificadora de la Actividad de Receptores/metabolismo , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Transducción de Señal , Bazo/inervación , Bazo/inmunología , FemeninoRESUMEN
Spleen marginal zone (MZ) B cells are important for antibody responses against blood-borne antigens. The signals they use to detect exposure to blood are not well defined. Here, using intravital two-photon microscopy in mice, we observe transient contacts between MZ B cells and red blood cells that are in flow. We show that MZ B cells use adhesion G-protein-coupled receptor ADGRE5 (CD97) for retention in the spleen. CD97 function in MZ B cells depends on its ability to undergo autoproteolytic cleavage and signaling via Gα13 and ARHGEF1. Red blood cell expression of the CD97 ligand CD55 is required for MZ B cell homeostasis. Applying a pulling force on CD97-transfected cells using an optical C-trap and CD55+ beads leads to accumulation of active RhoA and membrane retraction. Finally, we show that CD97 deficiency leads to a reduced T cell-independent IgM response. Thus, our studies provide evidence that MZ B cells use mechanosensing to position in a manner that enhances antibody responses against blood-borne antigens.
Asunto(s)
Linfocitos B , Tejido Linfoide , Ratones , Animales , Bazo/metabolismo , Transducción de Señal , Antígenos CD55/metabolismo , EritrocitosRESUMEN
While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combined fate mapping with profiling of the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ population that traffics to the intestine where it is maintained by the microbiota, providing a ready reservoir for the IL-23-driven generation of encephalitogenic GM-CSF+ IFN-γ+ CXCR6+ T cells. Our study defines a direct in vivo relationship between IL-17+ non-pathogenic and GM-CSF+ and IFN-γ+ pathogenic Th17 populations and provides a mechanism by which homeostatic intestinal Th17 cells direct extra-intestinal autoimmune disease.
Asunto(s)
Autoinmunidad , Intestinos/inmunología , Células Madre/metabolismo , Células Th17/inmunología , Animales , Movimiento Celular , Células Clonales , Encefalomielitis Autoinmune Experimental/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Homeostasis , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Ratones Endogámicos C57BL , Especificidad de Órganos , ARN/metabolismo , RNA-Seq , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores CXCR6/metabolismo , Receptores de Interleucina/metabolismo , Reproducibilidad de los Resultados , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Análisis de la Célula Individual , Bazo/metabolismoRESUMEN
Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.
Asunto(s)
Infecciones por Coronavirus/inmunología , Centro Germinal/inmunología , Neumonía Viral/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Anciano , Anciano de 80 o más Años , Linfocitos B/inmunología , COVID-19 , Femenino , Centro Germinal/patología , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Bazo/inmunología , Bazo/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT.
Asunto(s)
Envejecimiento/inmunología , Células Asesinas Naturales/citología , Linfopoyesis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/genética , Antígenos CD/metabolismo , Células Cultivadas , Niño , Femenino , Humanos , Inmunidad Innata , Mucosa Intestinal/citología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/fisiología , Pulmón/citología , Ganglios Linfáticos/citología , Masculino , Persona de Mediana Edad , Bazo/citologíaRESUMEN
The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69+ CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. VIDEO ABSTRACT.
Asunto(s)
Encéfalo/citología , Linfocitos T CD4-Positivos/metabolismo , Feto/citología , Microglía/citología , Microglía/metabolismo , Sinapsis/metabolismo , Adulto , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Escala de Evaluación de la Conducta , Células Sanguíneas/citología , Células Sanguíneas/metabolismo , Encéfalo/embriología , Encéfalo/metabolismo , Niño , Femenino , Feto/embriología , Humanos , Lectinas Tipo C/metabolismo , Pulmón/citología , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Neurogénesis/genética , Parabiosis , Células Piramidales/metabolismo , Células Piramidales/fisiología , Análisis de la Célula Individual , Bazo/citología , Bazo/metabolismo , Sinapsis/inmunología , TranscriptomaRESUMEN
Re-activation and clonal expansion of tumor-specific antigen (TSA)-reactive T cells are critical to the success of checkpoint blockade and adoptive transfer of tumor-infiltrating lymphocyte (TIL)-based therapies. There are no reliable markers to specifically identify the repertoire of TSA-reactive T cells due to their heterogeneous composition. We introduce FucoID as a general platform to detect endogenous antigen-specific T cells for studying their biology. Through this interaction-dependent labeling approach, intratumoral TSA-reactive CD4+, CD8+ T cells, and TSA-suppressive CD4+ T cells can be detected and separated from bystander T cells based on their cell-surface enzymatic fucosyl-biotinylation. Compared to bystander TILs, TSA-reactive TILs possess a distinct T cell receptor (TCR) repertoire and unique gene features. Although exhibiting a dysfunctional phenotype, TSA-reactive CD8+ TILs possess substantial capabilities of proliferation and tumor-specific killing. Featuring genetic manipulation-free procedures and a quick turnover cycle, FucoID should have the potential of accelerating the pace of personalized cancer treatment.
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Antígenos de Neoplasias/metabolismo , Comunicación Celular , Fucosa/metabolismo , Linfocitos T/inmunología , Linfocitos T/patología , Adulto , Secuencia de Aminoácidos , Animales , Biomarcadores de Tumor/metabolismo , Biotinilación , Efecto Espectador/inmunología , Linfocitos T CD8-positivos/inmunología , Membrana Celular/metabolismo , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Femenino , Fucosiltransferasas/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Helicobacter pylori/enzimología , Humanos , Inmunidad , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones Endogámicos C57BL , Péptidos/química , Fenotipo , Receptor de Muerte Celular Programada 1/metabolismo , Bazo/metabolismoRESUMEN
Current approaches to reducing the latent HIV reservoir entail first reactivating virus-containing cells to become visible to the immune system. A critical second step is killing these cells to reduce reservoir size. Endogenous cytotoxic T-lymphocytes (CTLs) may not be adequate because of cellular exhaustion and the evolution of CTL-resistant viruses. We have designed a universal CAR-T cell platform based on CTLs engineered to bind a variety of broadly neutralizing anti-HIV antibodies. We show that this platform, convertibleCAR-T cells, effectively kills HIV-infected, but not uninfected, CD4 T cells from blood, tonsil, or spleen and only when armed with anti-HIV antibodies. convertibleCAR-T cells also kill within 48 h more than half of the inducible reservoir found in blood of HIV-infected individuals on antiretroviral therapy. The modularity of convertibleCAR-T cell system, which allows multiplexing with several anti-HIV antibodies yielding greater breadth and control, makes it a promising tool for attacking the latent HIV reservoir.
Asunto(s)
Anticuerpos Antiidiotipos/farmacología , Infecciones por VIH/terapia , Inmunoterapia Adoptiva , Replicación Viral/genética , Animales , Anticuerpos Antiidiotipos/inmunología , Células HEK293 , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , VIH-1/patogenicidad , Humanos , Ratones , Tonsila Palatina/inmunología , Tonsila Palatina/metabolismo , Cultivo Primario de Células , Bazo/inmunología , Bazo/metabolismo , Linfocitos T Citotóxicos/inmunología , Latencia del Virus/inmunología , Replicación Viral/inmunologíaRESUMEN
Fasting is associated with improved outcomes in cancer. Here, we investigated the impact of fasting on natural killer (NK) cell anti-tumor immunity. Cyclic fasting improved immunity against solid and metastatic tumors in an NK cell-dependent manner. During fasting, NK cells underwent redistribution from peripheral tissues to the bone marrow (BM). In humans, fasting also reduced circulating NK cell numbers. NK cells in the spleen of fasted mice were metabolically rewired by elevated concentrations of fatty acids and glucocorticoids, augmenting fatty acid metabolism via increased expression of the enzyme CPT1A, and Cpt1a deletion impaired NK cell survival and function in this setting. In parallel, redistribution of NK cells to the BM during fasting required the trafficking mediators S1PR5 and CXCR4. These cells were primed by an increased pool of interleukin (IL)-12-expressing BM myeloid cells, which improved IFN-γ production. Our findings identify a link between dietary restriction and optimized innate immune responses, with the potential to enhance immunotherapy strategies.
Asunto(s)
Ayuno , Células Asesinas Naturales , Ratones Endogámicos C57BL , Animales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ratones , Humanos , Neoplasias/inmunología , Médula Ósea/inmunología , Médula Ósea/metabolismo , Ratones Noqueados , Interferón gamma/metabolismo , Interferón gamma/inmunología , Bazo/inmunología , Bazo/metabolismo , Inmunidad Innata/inmunología , Interleucina-12/metabolismo , Interleucina-12/inmunología , Receptores CXCR4/metabolismoRESUMEN
A highly multiplexed cytometric imaging approach, termed co-detection by indexing (CODEX), is used here to create multiplexed datasets of normal and lupus (MRL/lpr) murine spleens. CODEX iteratively visualizes antibody binding events using DNA barcodes, fluorescent dNTP analogs, and an in situ polymerization-based indexing procedure. An algorithmic pipeline for single-cell antigen quantification in tightly packed tissues was developed and used to overlay well-known morphological features with de novo characterization of lymphoid tissue architecture at a single-cell and cellular neighborhood levels. We observed an unexpected, profound impact of the cellular neighborhood on the expression of protein receptors on immune cells. By comparing normal murine spleen to spleens from animals with systemic autoimmune disease (MRL/lpr), extensive and previously uncharacterized splenic cell-interaction dynamics in the healthy versus diseased state was observed. The fidelity of multiplexed spatial cytometry demonstrated here allows for quantitative systemic characterization of tissue architecture in normal and clinically aberrant samples.
Asunto(s)
Anticuerpos/química , Modelos Animales de Enfermedad , Procesamiento de Imagen Asistido por Computador/métodos , Lupus Eritematoso Sistémico/patología , Sondas de Oligonucleótidos/química , Bazo/patología , Animales , Femenino , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos MRL lprRESUMEN
Understanding the physiology and genetics of human hypoxia tolerance has important medical implications, but this phenomenon has thus far only been investigated in high-altitude human populations. Another system, yet to be explored, is humans who engage in breath-hold diving. The indigenous Bajau people ("Sea Nomads") of Southeast Asia live a subsistence lifestyle based on breath-hold diving and are renowned for their extraordinary breath-holding abilities. However, it is unknown whether this has a genetic basis. Using a comparative genomic study, we show that natural selection on genetic variants in the PDE10A gene have increased spleen size in the Bajau, providing them with a larger reservoir of oxygenated red blood cells. We also find evidence of strong selection specific to the Bajau on BDKRB2, a gene affecting the human diving reflex. Thus, the Bajau, and possibly other diving populations, provide a new opportunity to study human adaptation to hypoxia tolerance. VIDEO ABSTRACT.
Asunto(s)
Adaptación Fisiológica , Contencion de la Respiración , Buceo , Tamaño de los Órganos , Hidrolasas Diéster Fosfóricas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Pueblo Asiatico , Eritrocitos/citología , Etnicidad , Femenino , Variación Genética , Genómica , Humanos , Hipoxia , Indonesia/etnología , Pulmón , Masculino , Persona de Mediana Edad , Oxígeno/fisiología , Fenotipo , Polimorfismo de Nucleótido Simple , Selección Genética , Bazo/fisiología , Población Blanca , Adulto JovenRESUMEN
Visceral adipose tissue (VAT) hosts a population of regulatory T (Treg) cells, with a unique phenotype, that controls local and systemic inflammation and metabolism. Generation of a T cell receptor transgenic mouse line, wherein VAT Tregs are highly enriched, facilitated study of their provenance, dependencies, and activities. We definitively established a role for T cell receptor specificity, uncovered an unexpected function for the primordial Treg transcription-factor, Foxp3, evidenced a cell-intrinsic role for interleukin-33 receptor, and ordered these dependencies within a coherent scenario. Genesis of the VAT-Treg phenotype entailed a priming step in the spleen, permitting them to exit the lymphoid organs and surveil nonlymphoid tissues, and a final diversification process within VAT, in response to microenvironmental cues. Understanding the principles of tissue-Treg biology is a prerequisite for precision-targeting strategies.
Asunto(s)
Grasa Intraabdominal/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T Reguladores/metabolismo , Animales , Ensamble y Desensamble de Cromatina , Factores de Transcripción Forkhead/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/genética , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Grasa Intraabdominal/inmunología , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , PPAR gamma/genética , PPAR gamma/metabolismo , Fenotipo , ARN/química , ARN/aislamiento & purificación , ARN/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Interleucina/metabolismo , Análisis de la Célula Individual , Bazo/inmunología , Bazo/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , TranscriptomaRESUMEN
Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119+CD45-CD71+ phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor ß (TGF-ß) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell-derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells' tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications.
Asunto(s)
Progresión de la Enfermedad , Eritroblastos/citología , Proteínas del Tejido Nervioso/sangre , Bazo/citología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Apoptosis , Carcinoma Hepatocelular/metabolismo , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Células Hep G2 , Humanos , Antígenos Comunes de Leucocito/metabolismo , Leucocitos/citología , Neoplasias Hepáticas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Invasividad Neoplásica/genética , Transducción de SeñalRESUMEN
CD8+ T cells responding to chronic infection adapt an altered differentiation program that provides some restraint on pathogen replication yet limits immunopathology. This adaptation is imprinted in stem-like cells and propagated to their progeny. Understanding the molecular control of CD8+ T cell differentiation in chronic infection has important therapeutic implications. Here, we find that the chemokine receptor CXCR3 is highly expressed on viral-specific stem-like CD8+ T cells and that one of its ligands, CXCL10, regulates the persistence and heterogeneity of responding CD8+ T cells in spleens of mice chronically infected with lymphocytic choriomeningitis virus. CXCL10 is produced by inflammatory monocytes and fibroblasts of the splenic red pulp, where it grants stem-like cells access to signals promoting differentiation and limits their exposure to pro-survival niches in the white pulp. Consequently, functional CD8+ T cell responses are greater in Cxcl10-/- mice and are associated with a lower viral set point.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Quimiocina CXCL10/metabolismo , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Monocitos/metabolismo , Receptores CXCR3/metabolismo , Bazo/patología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Diferenciación Celular , Proliferación Celular , Autorrenovación de las Células , Quimiocina CXCL10/genética , Enfermedad Crónica , Selección Clonal Mediada por Antígenos , Femenino , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CXCR3/genéticaRESUMEN
Tbet+CD11c+ B cells arise during type 1 pathogen challenge, aging, and autoimmunity in mice and humans. Here, we examined the developmental requirements of this B cell subset. In acute infection, T follicular helper (Tfh) cells, but not Th1 cells, drove Tbet+CD11c+ B cell generation through proximal delivery of help. Tbet+CD11c+ B cells developed prior to germinal center (GC) formation, exhibiting phenotypic and transcriptional profiles distinct from GC B cells. Fate tracking revealed that most Tbet+CD11c+ B cells developed independently of GC entry and cell-intrinsic Bcl6 expression. Tbet+CD11c+ and GC B cells exhibited minimal repertoire overlap, indicating distinct developmental pathways. As the infection resolved, Tbet+CD11c+ B cells localized to the marginal zone where splenic retention depended on integrins LFA-1 and VLA-4, forming a competitive memory subset that contributed to antibody production and secondary GC seeding upon rechallenge. Therefore, Tbet+CD11c+ B cells comprise a GC-independent memory subset capable of rapid and robust recall responses.
Asunto(s)
Linfocitos B/inmunología , Antígenos CD11/metabolismo , Subgrupos Linfocitarios/inmunología , Células T Auxiliares Foliculares/inmunología , Proteínas de Dominio T Box/metabolismo , Virosis/inmunología , Animales , Anticuerpos Antivirales/metabolismo , Linfocitos B/metabolismo , Diferenciación Celular/inmunología , Centro Germinal/inmunología , Alphainfluenzavirus/inmunología , Integrinas/metabolismo , Subgrupos Linfocitarios/metabolismo , Virus de la Coriomeningitis Linfocítica/inmunología , Células B de Memoria/inmunología , Células B de Memoria/metabolismo , Ratones , Bazo/inmunologíaRESUMEN
Interactions between intracellular bacteria and mononuclear phagocytes give rise to diverse cellular phenotypes that may determine the outcome of infection. Recent advances in single-cell RNA sequencing (scRNA-seq) have identified multiple subsets within the mononuclear population, but implications to their function during infection are limited. Here, we surveyed the mononuclear niche of intracellular Salmonella Typhimurium (S.Tm) during early systemic infection in mice. We described eclipse-like growth kinetics in the spleen, with a first phase of bacterial control mediated by tissue-resident red-pulp macrophages. A second phase involved extensive bacterial replication within a macrophage population characterized by CD9 expression. We demonstrated that CD9+ macrophages induced pathways for detoxificating oxidized lipids, that may be utilized by intracellular S.Tm. We established that CD9+ macrophages originated from non-classical monocytes (NCM), and NCM-depleted mice were more resistant to S.Tm infection. Our study defines macrophage subset-specific host-pathogen interactions that determine early infection dynamics and infection outcome of the entire organism.
Asunto(s)
Macrófagos/inmunología , Infecciones por Salmonella/inmunología , Salmonella typhimurium/fisiología , Bazo/inmunología , Animales , Interacciones Huésped-Patógeno , Humanos , Espacio Intracelular , Metabolismo de los Lípidos , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oxidación-Reducción , Análisis de la Célula Individual , Bazo/microbiología , Tetraspanina 29/metabolismoRESUMEN
Host defense against viruses and intracellular parasites depends on effector CD8(+) T cells, whose optimal clonal expansion, differentiation, and memory properties require signals from CD4(+) T cells. Here, we addressed the role of dendritic cell (DC) subsets in initial activation of the two T cell types and their co-operation. Surprisingly, initial priming of CD4(+) and CD8(+) T cells was spatially segregated within the lymph node and occurred on different DCs with temporally distinct patterns of antigen presentation via MHCI versus MHCII molecules. DCs that co-present antigen via both MHC molecules were detected at a later stage; these XCR1(+) DCs are the critical platform involved in CD4(+) T cell augmentation of CD8(+) T cell responses. These findings delineate the complex choreography of cellular interactions underlying effective cell-mediated anti-viral responses, with implications for basic DC subset biology, as well as for translational application to the development of vaccines that evoke optimal T cell immunity.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Comunicación Celular , Células Dendríticas/inmunología , Virus Vaccinia/fisiología , Vaccinia/inmunología , Animales , Presentación de Antígeno , Antígenos Virales/inmunología , Células Dendríticas/citología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ratones , Receptores de Quimiocina/genética , Bazo/citología , Bazo/inmunologíaRESUMEN
A subset of individuals infected with HIV-1 develops broadly neutralizing antibodies (bNAbs) that can prevent infection, but it has not yet been possible to elicit these antibodies by immunization. To systematically explore how immunization might be tailored to produce them, we generated mice expressing the predicted germline or mature heavy chains of a potent bNAb to the CD4 binding site (CD4bs) on the HIV-1 envelope glycoprotein (Env). Immunogens specifically designed to activate B cells bearing germline antibodies are required to initiate immune responses, but they do not elicit bNAbs. In contrast, native-like Env trimers fail to activate B cells expressing germline antibodies but elicit bNAbs by selecting for a restricted group of light chains bearing specific somatic mutations that enhance neutralizing activity. The data suggest that vaccination to elicit anti-HIV-1 antibodies will require immunization with a succession of related immunogens.
Asunto(s)
Anticuerpos Neutralizantes/genética , Anticuerpos Antivirales/genética , Técnicas de Sustitución del Gen , VIH-1/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Animales , Antígenos Virales , Linfocitos B/inmunología , Antígenos CD4/metabolismo , Infecciones por VIH/inmunología , Humanos , Ratones , Mutación , Bazo/citología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismoRESUMEN
In contrast to lymph nodes, the lymphoid regions of the spleen-the white pulp-are located deep within the organ, yielding the trafficking paths of T cells in the white pulp largely invisible. In an intravital microscopy tour de force reported in this issue of Immunity, Chauveau et al. show that T cells perform unidirectional, perivascular migration through the enigmatic marginal zone bridging channels.
Asunto(s)
Bazo , Linfocitos T , Movimiento Celular , Inmunidad , Ganglios LinfáticosRESUMEN
Lymphocyte homeostasis and immune surveillance require that T and B cells continuously recirculate between secondary lymphoid organs. Here, we used intravital microscopy to define lymphocyte trafficking routes within the spleen, an environment of open blood circulation and shear forces unlike other lymphoid organs. Upon release from arterioles into the red pulp sinuses, T cells latched onto perivascular stromal cells in a manner that was independent of the chemokine receptor CCR7 but sensitive to Gi protein-coupled receptor inhibitors. This latching sheltered T cells from blood flow and enabled unidirectional migration to the bridging channels and then to T zones, entry into which required CCR7. Inflammatory responses modified the chemotactic cues along the perivascular homing paths, leading to rapid block of entry. Our findings reveal a role for vascular structures in lymphocyte recirculation through the spleen, indicating the existence of separate entry and exit routes and that of a checkpoint located at the gate to the T zone.