RESUMEN
Maturation of B cells within germinal centers (GCs) generates diversified B cell pools and high-affinity B cell antigen receptors (BCRs) for pathogen clearance. Increased receptor affinity is achieved by iterative cycles of T cell-dependent, affinity-based B cell positive selection and clonal expansion by mechanisms hitherto incompletely understood. Here we found that, as part of a physiologic program, GC B cells repressed expression of decay-accelerating factor (DAF/CD55) and other complement C3 convertase regulators via BCL6, but increased the expression of C5b-9 inhibitor CD59. These changes permitted C3 cleavage on GC B cell surfaces without the formation of membrane attack complex and activated C3a- and C5a-receptor signals required for positive selection. Genetic disruption of this pathway in antigen-activated B cells by conditional transgenic DAF overexpression or deletion of C3a and C5a receptors limited the activation of mechanistic target of rapamycin (mTOR) in response to BCR-CD40 signaling, causing premature GC collapse and impaired affinity maturation. These results reveal that coordinated shifts in complement regulation within the GC provide crucial signals underlying GC B cell positive selection.
Asunto(s)
Linfocitos B/inmunología , Activación de Complemento , Complemento C3a/metabolismo , Complemento C5a/metabolismo , Centro Germinal/inmunología , Animales , Animales Modificados Genéticamente , Linfocitos B/metabolismo , Antígenos CD55/genética , Antígenos CD55/metabolismo , Antígenos CD59/metabolismo , Línea Celular Tumoral , Hematopoyesis Clonal/inmunología , Centro Germinal/citología , Centro Germinal/metabolismo , Humanos , Activación de Linfocitos , Ratones , Tonsila Palatina/citología , Tonsila Palatina/patología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Receptor de Anafilatoxina C5a/genética , Receptor de Anafilatoxina C5a/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores de Complemento/genética , Receptores de Complemento/metabolismo , Transducción de Señal/inmunología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Animales , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/terapia , Susceptibilidad a Enfermedades , Humanos , Inmunidad Innata , Memoria Inmunológica , Inflamación/inmunología , Inflamación/virología , Linfocitos/inmunología , Células Mieloides/inmunología , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/patología , Neumonía Viral/terapia , SARS-CoV-2RESUMEN
Cytometric immunophenotyping is a powerful tool to discover and implement T-cell biomarkers of type 1 diabetes (T1D) progression and response to clinical therapy. Although many discovery-based T-cell biomarkers have been described, to date, no such markers have been widely adopted in standard practice. The heterogeneous nature of T1D and lack of standardized assays and experimental design across studies is a major barrier to the broader adoption of T-cell immunophenotyping assays. There is an unmet need to harmonize the design of immunophenotyping assays, including those that measure antigen-agnostic cell populations, such that data collected from different clinical trial sites and T1D cohorts are comparable, yet account for cohort-specific features and different drug mechanisms of action. In these Guidelines, we aim to provide expert advice on how to unify aspects of study design and practice. We provide recommendations for defining cohorts, method implementation, as well as tools for data analysis and reporting by highlighting and building on selected successes. Harmonization of cytometry-based T-cell assays will allow researchers to better integrate findings across trials, ultimately enabling the identification and validation of biomarkers of disease progression and treatment response in T1D.
Asunto(s)
Diabetes Mellitus Tipo 1 , Biomarcadores/análisis , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/terapia , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación , Linfocitos TRESUMEN
Pathogen-specific memory T cells (TM) contribute to enhanced immune protection under conditions of reinfection, and their effective recruitment into a recall response relies, in part, on cues imparted by chemokines that coordinate their spatiotemporal positioning. An integrated perspective, however, needs to consider TM as a potentially relevant chemokine source themselves. In this study, we employed a comprehensive transcriptional/translational profiling strategy to delineate the identities, expression patterns, and dynamic regulation of chemokines produced by murine pathogen-specific TM CD8+TM, and to a lesser extent CD4+TM, are a prodigious source for six select chemokines (CCL1/3/4/5, CCL9/10, and XCL1) that collectively constitute a prominent and largely invariant signature across acute and chronic infections. Notably, constitutive CCL5 expression by CD8+TM serves as a unique functional imprint of prior antigenic experience; induced CCL1 production identifies highly polyfunctional CD8+ and CD4+TM subsets; long-term CD8+TM maintenance is associated with a pronounced increase of XCL1 production capacity; chemokines dominate the earliest stages of the CD8+TM recall response because of expeditious synthesis/secretion kinetics (CCL3/4/5) and low activation thresholds (CCL1/3/4/5/XCL1); and TM chemokine profiles modulated by persisting viral Ags exhibit both discrete functional deficits and a notable surplus. Nevertheless, recall responses and partial virus control in chronic infection appear little affected by the absence of major TM chemokines. Although specific contributions of TM-derived chemokines to enhanced immune protection therefore remain to be elucidated in other experimental scenarios, the ready visualization of TM chemokine-expression patterns permits a detailed stratification of TM functionalities that may be correlated with differentiation status, protective capacities, and potential fates.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Quimiocinas/inmunología , Memoria Inmunológica , Infecciones/inmunología , Enfermedad Aguda , Animales , Quimiocinas/genética , Enfermedad Crónica , Infecciones/genética , Ratones , Ratones Endogámicos BALB C , Ratones NoqueadosRESUMEN
The choreography of complex immune responses, including the priming, differentiation, and modulation of specific effector T cell populations generated in the immediate wake of an acute pathogen challenge, is in part controlled by chemokines, a large family of mostly secreted molecules involved in chemotaxis and other patho/physiological processes. T cells are both responsive to various chemokine cues and a relevant source for certain chemokines themselves; yet, the actual range, regulation, and role of effector T cell-derived chemokines remains incompletely understood. In this study, using different in vivo mouse models of viral and bacterial infection as well as protective vaccination, we have defined the entire spectrum of chemokines produced by pathogen-specific CD8+ and CD4+T effector cells and delineated several unique properties pertaining to the temporospatial organization of chemokine expression patterns, synthesis and secretion kinetics, and cooperative regulation. Collectively, our results position the "T cell chemokine response" as a notably prominent, largely invariant, yet distinctive force at the forefront of pathogen-specific effector T cell activities and establish novel practical and conceptual approaches that may serve as a foundation for future investigations into the role of T cell-produced chemokines in infectious and other diseases.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Quimiocinas/inmunología , Infecciones/inmunología , Animales , Quimiocinas/genética , Infecciones/genética , Ratones , Ratones Endogámicos BALB C , Ratones NoqueadosRESUMEN
The determinants of protective CD8+ memory T cell (CD8+TM) immunity remain incompletely defined and may in fact constitute an evolving agency as aging CD8+TM progressively acquire enhanced rather than impaired recall capacities. Here, we show that old as compared to young antiviral CD8+TM more effectively harness disparate molecular processes (cytokine signaling, trafficking, effector functions, and co-stimulation/inhibition) that in concert confer greater secondary reactivity. The relative reliance on these pathways is contingent on the nature of the secondary challenge (greater for chronic than acute viral infections) and over time, aging CD8+TM re-establish a dependence on the same accessory signals required for effective priming of naïve CD8+T cells in the first place. Thus, our findings reveal a temporal regulation of complementary recall response determinants that is consistent with the recently proposed "rebound model" according to which aging CD8+TM properties are gradually aligned with those of naïve CD8+T cells; our identification of a broadly diversified collection of immunomodulatory targets may further provide a foundation for the potential therapeutic "tuning" of CD8+TM immunity.
Asunto(s)
Envejecimiento/inmunología , Infecciones por Arenaviridae/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Memoria Inmunológica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Recuerdo Mental/fisiología , Animales , Infecciones por Arenaviridae/virología , Citocinas/metabolismo , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Aging of established antiviral T cell memory can foster a series of progressive adaptations that paradoxically improve rather than compromise protective CD8+ T cell immunity. We now provide evidence that this gradual evolution, the pace of which is contingent on the precise context of the primary response, also impinges on the molecular mechanisms that regulate CD8+ memory T cell (TM) homeostasis. Over time, CD8+ TM generated in the wake of an acute infection with the natural murine pathogen lymphocytic choriomeningitis virus become more resistant to apoptosis and acquire enhanced cytokine responsiveness without adjusting their homeostatic proliferation rates; concurrent metabolic adaptations promote increased CD8+ TM quiescence and fitness but also impart the reacquisition of a partial effector-like metabolic profile; and a gradual redistribution of aging CD8+ TM from blood and nonlymphoid tissues to lymphatic organs results in CD8+ TM accumulations in bone marrow, splenic white pulp, and, particularly, lymph nodes. Altogether, these data demonstrate how temporal alterations of fundamental homeostatic determinants converge to render aged CD8+ TM poised for greater recall responses.
Asunto(s)
Envejecimiento/inmunología , Linfocitos T CD8-positivos/fisiología , Memoria Inmunológica/inmunología , Ganglios Linfáticos/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Animales , Antígenos Virales/inmunología , Movimiento Celular , Supervivencia Celular , Células Cultivadas , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
Dendritic cell vaccines are a promising strategy for the treatment of cancer and infectious diseases but have met with mixed success. We report on a lentiviral vector-based dendritic cell vaccine strategy that generates a cluster of differentiation 8 (CD8) T cell response that is much stronger than that achieved by standard peptide-pulsing approaches. The strategy was tested in the mouse lymphocytic choriomeningitis virus (LCMV) model. Bone marrow-derived dendritic cells from SAMHD1 knockout mice were transduced with a lentiviral vector expressing the GP33 major-histocompatibility-complex (MHC)-class-I-restricted peptide epitope and CD40 ligand (CD40L) and injected into wild-type mice. The mice were highly protected against acute and chronic variant CL-13 LCMVs, resulting in a 100-fold greater decrease than that achieved with peptide epitope-pulsed dendritic cells. Inclusion of an MHC-class-II-restricted epitope in the lentiviral vector further increased the CD8 T cell response and resulted in antigen-specific CD8 T cells that exhibited a phenotype associated with functional cytotoxic T cells. The vaccination synergized with checkpoint blockade to reduce the viral load of mice chronically infected with CL-13 to an undetectable level. The strategy improves upon current dendritic cell vaccine strategies; is applicable to the treatment of disease, including AIDS and cancer; and supports the utility of Vpx-containing vectors.
Asunto(s)
Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Vectores Genéticos , Inhibidores de Puntos de Control Inmunológico/farmacología , Lentivirus , Vacunas Virales/inmunología , Virosis/prevención & control , Animales , Biomarcadores , Células Dendríticas/virología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Antígenos de Histocompatibilidad Clase II , Interacciones Huésped-Patógeno/inmunología , Humanos , Lentivirus/genética , Coriomeningitis Linfocítica/prevención & control , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Vacunas Virales/administración & dosificación , Virosis/etiología , Virosis/inmunologíaRESUMEN
Rapid activation and proliferative expansion of specific CD8(+) memory T (CD8(+) TM ) cells upon antigen re-encounter is a critical component of the adaptive immune response that confers enhanced immune protection. In this context, however, the requirements for costimulation in general, and CD28 signaling in particular, remain incompletely defined. In the current issue of the European Journal of Immunology, Fröhlich et al. [Eur. J. Immunol. 2016. 46: 1644-1655] provide definitive evidence that optimal elaboration of CD8(+) TM -cell recall responses is indeed contingent on CD28 expressed by these cells. Here, we discuss the "CD28 costimulation paradigm" in its historical context and highlight some of the unresolved complexities pertaining to CD28-dependent interactions that shape CD8(+) T-cell phenotypes, functionalities, and recall reactivity.
Asunto(s)
Antígenos CD28/genética , Memoria Inmunológica/genética , Animales , Antígeno B7-1/genética , Linfocitos T CD8-positivos/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/inmunologíaRESUMEN
BACKGROUND: An association between hepatitis C virus (HCV) and type 2 diabetes (T2D) is supported by numerous epidemiologic studies. We hypothesized that HCV could infect human pancreatic islet cells in vitro. METHODS: Measures of HCV RNA synthesis and protein production were used to evaluate HCV infection of pancreatic islets recovered from human donors. RESULTS: Significant co-staining of insulin and the HCV entry factor CD81 was observed in pancreatic islets. Positive- and negative-sense HCV RNA were detected in HCV-exposed islets at days 1, 3, 7, and 14 post-infection. The HCV core and NS3 proteins were expressed and increased with time providing further evidence of viral replication. Interferon and an HCV polymerase inhibitor reduced viral replication in islet cells. In HCV-infected islets, TNFα levels were elevated at days 1, 3, and 7 post-infection, while IL-6 levels were elevated at day 1 but not days 3 or 7. Overall, the expression of miR-122 was low in islets compared to the Huh7.5 hepatocyte-derived cell line, although the relative expression of miR-122 increased in islet cells after viral infection (1, 6.63, and 5.83 at days 1, 3, and 7, respectively). CONCLUSIONS: In this pilot study, viral infection was demonstrated in pancreatic islet cells from multiple donors using complementary measures of viral replication, thus providing evidence of in vitro infection. Altered cytokine expression may contribute to the development of insulin deficiency, and understanding the etiology of diabetes in individuals with HCV infection may facilitate the development of novel treatment modalities and prevention strategies. This in vitro system provides an important model for mechanistic studies of HCV-pancreas interactions and facilitates future studies of the potential impact of viral infection on islet cell function.
Asunto(s)
Hepacivirus/fisiología , Hepatitis C/virología , Islotes Pancreáticos/virología , Antivirales/farmacología , Células Cultivadas , Citocinas/metabolismo , Células HEK293 , Hepacivirus/efectos de los fármacos , Hepatitis C/sangre , Hepatocitos , Humanos , Interferón-alfa/farmacología , Islotes Pancreáticos/metabolismo , MicroARNs/metabolismo , ARN Viral , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sofosbuvir/farmacología , Proteínas no Estructurales Virales/metabolismo , Virión/fisiología , Internalización del Virus , Replicación Viral/efectos de los fármacos , Replicación Viral/fisiologíaRESUMEN
Ross River virus (RRV), chikungunya virus, and related alphaviruses cause debilitating polyarthralgia and myalgia. Mouse models of RRV and chikungunya virus have demonstrated a role for the adaptive immune response in the control of these infections. However, questions remain regarding the role for T cells in viral control, including the magnitude, location, and dynamics of CD8(+) T cell responses. To address these questions, we generated a recombinant RRV expressing the H-2(b)-restricted glycoprotein 33 (gp33) determinant derived from the glycoprotein of lymphocytic choriomeningitis virus. Using tetramers, we tracked gp33-specific CD8(+) T cells during RRV-lymphocytic choriomeningitis virus infection. We found that acute RRV infection induces activation of CD8(+) T cell responses in lymphoid and musculoskeletal tissues that peak from 10-14 d postinoculation, suggesting that CD8(+) T cells contribute to control of acute RRV infection. Mice genetically deficient for CD8(+) T cells or wild-type mice depleted of CD8(+) T cells had elevated RRV loads in skeletal muscle tissue, but not joint-associated tissues, at 14 d postinoculation, suggesting that the ability of CD8(+) T cells to control RRV infection is tissue dependent. Finally, adoptively transferred T cells were capable of reducing RRV loads in skeletal muscle tissue of Rag1(-/-) mice, indicating that T cells can contribute to the control of RRV infection in the absence of B cells and Ab. Collectively, these data demonstrate a role for T cells in the control of RRV infection and suggest that the antiviral capacity of T cells is controlled in a tissue-specific manner.
Asunto(s)
Infecciones por Alphavirus/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunidad Celular , Músculo Esquelético/inmunología , Virus del Río Ross/inmunología , Infecciones por Alphavirus/genética , Infecciones por Alphavirus/patología , Animales , Linfocitos T CD8-positivos/patología , Antígeno de Histocompatibilidad H-2D/genética , Antígeno de Histocompatibilidad H-2D/inmunología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/inmunología , Ratones , Ratones Noqueados , Músculo Esquelético/patología , Músculo Esquelético/virología , Factores de Tiempo , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
NK cells are innate lymphoid cells important for immune surveillance, identifying and responding to stress, infection, and/or transformation. Whereas conventional NK (cNK) cells circulate systemically, many NK cells reside in tissues where they appear to be poised to locally regulate tissue function. In the present study, we tested the contribution of tissue-resident NK (trNK) cells to tissue homeostasis by studying ischemic injury in the mouse kidney. Parabiosis experiments demonstrate that the kidney contains a significant fraction of trNK cells under homeostatic conditions. Kidney trNK cells developed independent of NFIL3 and T-bet, and they expressed a distinct cell surface phenotype as compared with cNK cells. Among these, trNK cells had reduced asialo-GM1 (AsGM1) expression relative to cNK cells, a phenotype observed in trNK cells across multiple organs and mouse strains. Strikingly, anti-AsGM1 Ab treatment, commonly used as an NK cell-depleting regimen, resulted in a robust and selective depletion of cNKs, leaving trNKs largely intact. Using this differential depletion, we tested the relative contribution of cNK and trNK cells in ischemic kidney injury. Whereas anti-NK1.1 Ab effectively depleted both trNK and cNK cells and protected against ischemic/reperfusion injury, anti-AsGM1 Ab preferentially depleted cNK cells and failed to protect against injury. These data demonstrate unanticipated specificity of anti-AsGM1 Ab depletion on NK cell subsets and reveal a new approach to study the contributions of cNK and trNK cells in vivo. In total, these data demonstrate that trNK cells play a key role in modulating local responses to ischemic tissue injury in the kidney and potentially other organs.
Asunto(s)
Anticuerpos/farmacología , Gangliósido G(M1)/inmunología , Isquemia/inmunología , Enfermedades Renales/inmunología , Riñón/irrigación sanguínea , Riñón/inmunología , Células Asesinas Naturales/inmunología , Animales , Gangliósido G(M1)/antagonistas & inhibidores , Isquemia/patología , Riñón/patología , Enfermedades Renales/patología , Células Asesinas Naturales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones NoqueadosAsunto(s)
Inmunidad , Memoria Inmunológica , Animales , Interacciones Huésped-Patógeno/inmunología , HumanosRESUMEN
Generation of functional CD8 + T cell memory typically requires engagement of CD4 + T cells. However, in certain scenarios, such as acutely-resolving viral infections, effector (T E ) and subsequent memory (T M ) CD8 + T cell formation appear impervious to a lack of CD4 + T cell help during priming. Nonetheless, such "helpless" CD8 + T M respond poorly to pathogen rechallenge. At present, the origin and long-term evolution of helpless CD8 + T cell memory remain incompletely understood. Here, we demonstrate that helpless CD8 + T E differentiation is largely normal but a multiplicity of helpless CD8 T M defects, consistent with impaired memory maturation, emerge as a consequence of prolonged yet finite exposure to cognate antigen. Importantly, these defects resolve over time leading to full restoration of CD8 + T M potential and recall capacity. Our findings provide a unified explanation for helpless CD8 + T cell memory and emphasize an unexpected CD8 + T M plasticity with implications for vaccination strategies and beyond.
RESUMEN
The lymphocytic choriomeningitis virus (LCMV) system constitutes one of the most widely used models for the study of infectious disease and the regulation of virus-specific T cell immunity. However, with respect to the activity of costimulatory and associated regulatory pathways, LCMV-specific T cell responses have long been regarded as relatively independent and thus distinct from the regulation of T cell immunity directed against many other viral pathogens. Here, we have reevaluated the contribution of CD28-CD80/86 costimulation in the LCMV system by use of CD80/86-deficient mice, and our results demonstrate that a disruption of CD28-CD80/86 signaling compromises the magnitude, phenotype, and/or functionality of LCMV-specific CD8(+) and/or CD4(+) T cell populations in all stages of the T cell response. Notably, a profound inhibition of secondary T cell immunity in LCMV-immune CD80/86-deficient mice emerged as a composite of both defective memory T cell development and a specific requirement for CD80 but not CD86 in the recall response, while a related experimental scenario of CD28-dependent yet CD80/86-independent secondary CD8(+) T cell immunity suggests the existence of a CD28 ligand other than CD80/86. Furthermore, we provide evidence that regulatory T cells (T(REG)s), the homeostasis of which is altered in CD80/86(-/-) mice, contribute to restrained LCMV-specific CD8(+) T cell responses in the presence of CD80/86. Our observations can therefore provide a more coherent perspective on CD28-CD80/86 costimulation in antiviral T cell immunity that positions the LCMV system within a shared context of multiple defects that virus-specific T cells acquire in the absence of CD28-CD80/86 costimulation.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Antígeno B7-1/genética , Antígeno B7-1/inmunología , Antígeno B7-2/genética , Antígeno B7-2/inmunología , Antígenos CD28/genética , Antígenos CD28/inmunología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/virología , Células Cultivadas , Femenino , Humanos , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Subgrupos de Linfocitos T/virologíaRESUMEN
Homeostasis in the immune system encompasses the mechanisms governing maintenance of a functional and diverse pool of lymphocytes, thus guaranteeing immunity to pathogens while remaining self-tolerant. Antigen-naïve T cells rely on survival signals through contact with self-peptide-loaded major histocompatibility complex (MHC) molecules plus interleukin (IL)-7. Conversely, antigen-experienced (memory) T cells are typically MHC-independent and they survive and undergo periodic homeostatic proliferation through contact with both IL-7 and IL-15. Also, non-conventional γδ T cells rely on a mix of IL-7 and IL-15 for their homeostasis, whereas natural killer cells are mainly dependent on contact with IL-15. Homeostasis of CD4(+) T regulatory cells is different in being chiefly regulated by contact with IL-2. Notably, increased levels of these cytokines cause expansion of responsive lymphocytes, such as found in lymphopenic hosts or following cytokine injection, whereas reduced cytokine levels cause a decline in cell numbers.
Asunto(s)
Homeostasis , Células Asesinas Naturales/inmunología , Linfocitos T/inmunología , Citocinas/metabolismo , Citocinas/fisiología , Memoria Inmunológica , Modelos Inmunológicos , Receptores de Antígenos de Linfocitos T/fisiología , Transducción de SeñalRESUMEN
The thymus is critical for the establishment of a functional and self-tolerant adaptive immune system but involutes with age, resulting in reduced naive T cell output. Generation of a functional human thymus from human pluripotent stem cells (hPSCs) is an attractive regenerative strategy. Direct differentiation of thymic epithelial progenitors (TEPs) from hPSCs has been demonstrated in vitro, but functional thymic epithelial cells (TECs) only form months after transplantation of TEPs in vivo. We show the generation of TECs in vitro in isogenic stem cell-derived thymic organoids (sTOs) consisting of TEPs, hematopoietic progenitor cells, and mesenchymal cells, differentiated from the same hPSC line. sTOs support T cell development, express key markers of negative selection, including the autoimmune regulator (AIRE) protein, and facilitate regulatory T cell development. sTOs provide the basis for functional patient-specific thymic organoid models, allowing for the study of human thymus function, T cell development, and transplant immunity.
Asunto(s)
Células Madre Pluripotentes , Timo , Humanos , Linfocitos T , Células Epiteliales/metabolismo , Diferenciación Celular/fisiología , OrganoidesRESUMEN
During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1-positive (PD-1+) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cell factor 1 (TCF-1) and high levels of the costimulatory molecule CD28. Here, we demonstrate that sustained CD28 costimulation is required for maintenance of antiviral T cells during chronic infection. Low-level CD28 engagement preserved mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation into TCF-1neg exhausted CD8 T cells (Tex). Furthermore, enhanced differentiation by CD28 engagement did not reduce the Tpex pool. Together, these findings demonstrate that continuous CD28 engagement is needed to sustain PD-1+ CD8 T cells and suggest that increasing CD28 signaling promotes Tpex differentiation into more functional effector-like Tex, possibly without compromising long-term responses.
Asunto(s)
Antígenos CD28 , Factor 1 de Transcripción de Linfocitos T , Factor 1 de Transcripción de Linfocitos T/genética , Receptor de Muerte Celular Programada 1 , Linfocitos T CD8-positivos , Diferenciación Celular , Factores de TranscripciónRESUMEN
Preservation and expansion of ß-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPß) is a nuclear effector of hyperglycemic stress occurring in ß-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPß is necessary for adaptive ß-cell expansion in response to metabolic challenges. Conversely, chronic excessive ß-cell-specific overexpression of ChREBPß results in loss of ß-cell identity, apoptosis, loss of ß-cell mass, and diabetes. Furthermore, ß-cell "glucolipotoxicity" can be prevented by deletion of ChREBPß. Moreover, ChREBPß-mediated cell death is mitigated by overexpression of the alternate CHREBP gene product, ChREBPα, or by activation of the antioxidant Nrf2 pathway in rodent and human ß-cells. We conclude that ChREBPß, whether adaptive or maladaptive, is an important determinant of ß-cell fate and a potential target for the preservation of ß-cell mass in diabetes.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Células Secretoras de Insulina , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Retroalimentación , Glucosa/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismoRESUMEN
Concerns that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), may cause new-onset diabetes persist in an evolving research landscape, and precise risk assessment is hampered by, at times, conflicting evidence. Here, leveraging comprehensive single-cell analyses of in vitro SARS-CoV-2-infected human pancreatic islets, we demonstrate that productive infection is strictly dependent on the SARS-CoV-2 entry receptor ACE2 and targets practically all pancreatic cell types. Importantly, the infection remains highly circumscribed and largely non-cytopathic and, despite a high viral burden in infected subsets, promotes only modest cellular perturbations and inflammatory responses. Similar experimental outcomes are also observed after islet infection with endemic coronaviruses. Thus, the limits of pancreatic SARS-CoV-2 infection, even under in vitro conditions of enhanced virus exposure, challenge the proposition that in vivo targeting of ß cells by SARS-CoV-2 precipitates new-onset diabetes. Whether restricted pancreatic damage and immunological alterations accrued by COVID-19 increase cumulative diabetes risk, however, remains to be evaluated.