RESUMEN
CD8+ T cells are classically recognized as adaptive lymphocytes based on their ability to recognize specific foreign antigens and mount memory responses. However, recent studies indicate that some antigen-inexperienced CD8+ T cells can respond to innate cytokines alone in the absence of cognate T cell receptor stimulation, a phenomenon referred to as bystander activation. Here, we demonstrate that neonatal CD8+ T cells undergo a robust and diverse program of bystander activation, which corresponds to enhanced innate-like protection against unrelated pathogens. Using a multi-omics approach, we found that the ability of neonatal CD8+ T cells to respond to innate cytokines derives from their capacity to undergo rapid chromatin remodeling, resulting in the usage of a distinct set of enhancers and transcription factors typically found in innate-like T cells. We observed that the switch between innate and adaptive functions in the CD8+ T cell compartment is mediated by changes in the abundance of distinct subsets of cells. The innate CD8+ T cell subset that predominates in early life was also present in adult mice and humans. Our findings provide support for the layered immune hypothesis and indicate that the CD8+ T cell compartment is more functionally diverse than previously thought.
Asunto(s)
Linfocitos T CD8-positivos , Inmunidad Innata , Humanos , Adulto , Ratones , Animales , Citocinas , Subgrupos de Linfocitos T , AntígenosRESUMEN
It is well known that males and females respond differently to intracellular pathogens. Females mount a more robust immune response than males, which decreases their susceptibility to infection but comes at the cost of increasing immunopathology. However, the underlying basis for sex-specific differences in the CD8+ T cell response to infection remains poorly understood. In this study, we show that female CD8+ T cells have an intrinsic propensity to become short-lived effectors, whereas male CD8+ T cells give rise to more memory precursor effector cells after murine infection with either a virus (vaccinia virus) or bacteria (Listeria monocytogenes). Interestingly, we found that the propensity of female CD8+ T cells to form short-lived effectors is not because they respond to lower amounts of cognate Ag but rather because they have an enhanced capacity to respond to IL-12, which facilitates more effector cell differentiation at each round of cell division. Our findings provide key insights into the sex-based immunological differences that underlie variations in the susceptibility to infection in males and females. ImmunoHorizons, 2019, 3: 121-132.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Interacciones Huésped-Patógeno , Infecciones/etiología , Infecciones/metabolismo , Interleucina-12/metabolismo , Traslado Adoptivo , Animales , Antígenos/inmunología , Linfocitos T CD8-positivos/citología , Diferenciación Celular/inmunología , Modelos Animales de Enfermedad , Femenino , Interacciones Huésped-Patógeno/inmunología , Inmunofenotipificación , Masculino , Ratones , Ratones Noqueados , Factores SexualesRESUMEN
Heterogeneity is a hallmark feature of the adaptive immune system in vertebrates. Following infection, naive T cells differentiate into various subsets of effector and memory T cells, which help to eliminate pathogens and maintain long-term immunity. The current model suggests there is a single lineage of naive T cells that give rise to different populations of effector and memory T cells depending on the type and amounts of stimulation they encounter during infection. Here, we have discovered that multiple sub-populations of cells exist in the naive CD8+ T cell pool that are distinguished by their developmental origin, unique transcriptional profiles, distinct chromatin landscapes, and different kinetics and phenotypes after microbial challenge. These data demonstrate that the naive CD8+ T cell pool is not as homogeneous as previously thought and offers a new framework for explaining the remarkable heterogeneity in the effector and memory T cell subsets that arise after infection.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Genes del Desarrollo , Listeria monocytogenes/patogenicidad , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Cromatina/metabolismo , Citocinas/farmacología , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/metabolismo , Memoria Inmunológica , Interferón gamma/metabolismo , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Listeria monocytogenes/metabolismo , Ratones , Ratones Endogámicos C57BL , Análisis de Componente Principal , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Timo/trasplante , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , TranscriptomaRESUMEN
Macrophages are common targets for infection and innate immune activation by many pathogenic viruses including the neurotropic Theiler's Murine Encephalomyelitis Virus (TMEV). As both infection and innate activation of macrophages are key determinants of viral pathogenesis especially in the central nervous system (CNS), an analysis of macrophage growth factors on these events was performed. C3H mouse bone-marrow cells were differentiated in culture using either recombinant macrophage colony stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), inoculated with TMEV (BeAn) and analyzed at various times thereafter. Cytokine RNA and protein analysis, virus titers, and flow cytometry were performed to characterize virological parameters under these culture conditions. GM-CSF-differentiated macrophages showed higher levels of TMEV viral RNA and proinflammatory molecules compared to infected M-CSF-differentiated cells. Thus, GM-CSF increases both TMEV infection and TMEV-induced activation of macrophages compared to that seen with M-CSF. Moreover, while infectious viral particles decreased from a peak at 12h to undetectable levels at 48h post infection, TMEV viral RNA remained higher in GM-CSF- compared to M-CSF-differentiated macrophages in concert with increased proinflammatory gene expression. Analysis of a possible basis for these differences determined that glycolytic rates contributed to heightened virus replication and proinflammatory cytokine secretion in GM-CSF compared to M-CSF-differentiated macrophages. In conclusion, we provide evidence implicating a role for GM-CSF in promoting virus replication and proinflammatory cytokine expression in macrophages, indicating that GM-CSF may be a key factor for TMEV infection and the induction of chronic TMEV-induced immunopathogenesis in the CNS.
Asunto(s)
Infecciones por Cardiovirus/etiología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Activación de Macrófagos , Factor Estimulante de Colonias de Macrófagos/inmunología , Theilovirus/patogenicidad , Animales , Infecciones por Cardiovirus/inmunología , Infecciones por Cardiovirus/virología , Diferenciación Celular/inmunología , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/genética , Citocinas/metabolismo , Glucólisis , Macrófagos/inmunología , Macrófagos/patología , Macrófagos/virología , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Viral/genética , Theilovirus/genética , Theilovirus/aislamiento & purificación , Replicación Viral/inmunologíaRESUMEN
During the ontogeny of the mammalian immune system, distinct lineages of cells arise from fetal and adult hematopoietic stem cells (HSCs) during specific stages of development. However, in some cases, the same immune cell type is produced by both HSC populations, resulting in the generation of phenotypically similar cells with distinct origins and divergent functional properties. In this report, we demonstrate that neonatal CD8+ T cells preferentially become short-lived effectors and adult CD8+ T cells selectively form long-lived memory cells after infection because they are derived from distinct progenitor cells. Notably, we find that naïve neonatal CD8+ T cells originate from a progenitor cell that is distinguished by expression of Lin28b. Remarkably, ectopic expression of Lin28b enables adult progenitors to give rise to CD8+ T cells that are phenotypically and functionally analogous to those found in neonates. These findings suggest that neonatal and adult CD8+ T cells belong to separate lineages of CD8+ T cells, and potentially explain why it is challenging to elicit memory CD8+ T cells in early life.
Asunto(s)
Células Madre Adultas/citología , Linfocitos T CD8-positivos/citología , Células Madre Fetales/citología , Feto/citología , Células Madre Adultas/metabolismo , Envejecimiento , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Proteínas de Unión al ADN/metabolismo , Células Madre Fetales/metabolismo , Perfilación de la Expresión Génica , Memoria Inmunológica , Ratones Endogámicos C57BL , Fenotipo , Proteínas de Unión al ARN , Timo/citologíaRESUMEN
Virus-induced myositis is an emerging global affliction that remains poorly characterized with few treatment options. Moreover, muscle-tropic viruses often spread to the CNS, causing dramatically increased morbidity. Therefore, there is an urgent need to explore genetic factors involved in this class of human disease. This report investigates critical innate immune pathways affecting murine virus-induced myositis. Of particular importance, the key immune regulator src homology region 2 domain-containing phosphatase 1 (SHP-1), which normally suppresses macrophage-mediated inflammation, is a major factor in promoting clinical disease in muscle. We show that Theiler's murine encephalomyelitis virus (TMEV) infection of skeletal myofibers induces inflammation and subsequent dystrophic calcification, with loss of ambulation in wild-type (WT) mice. Surprisingly, although similar extensive myofiber infection and inflammation are observed in SHP-1(-/-) mice, these mice neither accumulate dead calcified myofibers nor lose ambulation. Macrophages were the predominant effector cells infiltrating WT and SHP-1(-/-) muscle, and an increased infiltration of immature monocytes/macrophages correlated with an absence of clinical disease in SHP-1(-/-) mice, whereas mature M1-like macrophages corresponded with increased myofiber degeneration in WT mice. Furthermore, blocking SHP-1 activation in WT macrophages blocked virus-induced myofiber degeneration, and pharmacologic ablation of macrophages inhibited muscle calcification in TMEV-infected WT animals. These data suggest that, following TMEV infection of muscle, SHP-1 promotes M1 differentiation of infiltrating macrophages, and these inflammatory macrophages are likely involved in damaging muscle fibers. These findings reveal a pathological role for SHP-1 in promoting inflammatory macrophage differentiation and myofiber damage in virus-infected skeletal muscle, thus identifying SHP-1 and M1 macrophages as essential mediators of virus-induced myopathy.