RESUMEN
The discovery of tissue-resident innate lymphoid cell populations effecting different forms of type 1, 2, and 3 immunity; tissue repair; and immune regulation has transformed our understanding of mucosal immunity and allergy. The emerging complexity of these populations along with compounding issues of redundancy and plasticity raise intriguing questions about their precise lineage relationship. Here we review advances in mapping the emergence of these lineages from early lymphoid precursors. We discuss the identification of a common innate lymphoid cell precursor characterized by transient expression of the transcription factor PLZF, and the lineage relationships of innate lymphoid cells with conventional natural killer cells and lymphoid tissue inducer cells. We also review the rapidly growing understanding of the network of transcription factors that direct the development of these lineages.
Asunto(s)
Diferenciación Celular , Hipersensibilidad/inmunología , Inmunidad Innata , Linfocitos/inmunología , Células Progenitoras Linfoides/inmunología , Animales , Linaje de la Célula , Citocinas/metabolismo , Regulación de la Expresión Génica/inmunología , Redes Reguladoras de Genes , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
The microbiota plays a fundamental role in regulating host immunity. However, the processes involved in the initiation and regulation of immunity to the microbiota remain largely unknown. Here, we show that the skin microbiota promotes the discrete expression of defined endogenous retroviruses (ERVs). Keratinocyte-intrinsic responses to ERVs depended on cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING) signaling and promoted the induction of commensal-specific T cells. Inhibition of ERV reverse transcription significantly impacted these responses, resulting in impaired immunity to the microbiota and its associated tissue repair function. Conversely, a lipid-enriched diet primed the skin for heightened ERV- expression in response to commensal colonization, leading to increased immune responses and tissue inflammation. Together, our results support the idea that the host may have co-opted its endogenous virome as a means to communicate with the exogenous microbiota, resulting in a multi-kingdom dialog that controls both tissue homeostasis and inflammation.
Asunto(s)
Retrovirus Endógenos/fisiología , Homeostasis , Inflamación/microbiología , Inflamación/patología , Microbiota , Animales , Bacterias/metabolismo , Cromosomas Bacterianos/genética , Dieta Alta en Grasa , Inflamación/inmunología , Inflamación/virología , Interferón Tipo I/metabolismo , Queratinocitos/metabolismo , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Nucleotidiltransferasas/metabolismo , Retroelementos/genética , Transducción de Señal , Piel/inmunología , Piel/microbiología , Linfocitos T/inmunología , Transcripción GenéticaRESUMEN
Cancer cells must evade immune responses at distant sites to establish metastases. The lung is a frequent site for metastasis. We hypothesized that lung-specific immunoregulatory mechanisms create an immunologically permissive environment for tumor colonization. We found that T-cell-intrinsic expression of the oxygen-sensing prolyl-hydroxylase (PHD) proteins is required to maintain local tolerance against innocuous antigens in the lung but powerfully licenses colonization by circulating tumor cells. PHD proteins limit pulmonary type helper (Th)-1 responses, promote CD4(+)-regulatory T (Treg) cell induction, and restrain CD8(+) T cell effector function. Tumor colonization is accompanied by PHD-protein-dependent induction of pulmonary Treg cells and suppression of IFN-γ-dependent tumor clearance. T-cell-intrinsic deletion or pharmacological inhibition of PHD proteins limits tumor colonization of the lung and improves the efficacy of adoptive cell transfer immunotherapy. Collectively, PHD proteins function in T cells to coordinate distinct immunoregulatory programs within the lung that are permissive to cancer metastasis. PAPERCLIP.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Pulmón/inmunología , Oxígeno/metabolismo , Prolil Hidroxilasas/metabolismo , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/enzimología , Glucólisis/inmunología , Interferón gamma/inmunología , Pulmón/patología , Neoplasias Pulmonares/terapia , Activación de Linfocitos , Ratones , Ratones Noqueados , Metástasis de la Neoplasia , Neuropilina-1/metabolismo , Prolil Hidroxilasas/genética , Linfocitos T Reguladores/enzimología , Células TH1/enzimología , Células TH1/inmunologíaRESUMEN
The precise lineage relationship between innate lymphoid cells (ILCs) and lymphoid tissue-inducer (LTi) cells is poorly understood. Using single-cell multiplex transcriptional analysis of 100 lymphoid genes and single-cell cultures of fetal liver precursor cells, we identified the common proximal precursor to these lineages and found that its bifurcation was marked by differential induction of the transcription factors PLZF and TCF1. Acquisition of individual effector programs specific to the ILC subsets ILC1, ILC2 and ILC3 was initiated later, at the common ILC precursor stage, by transient expression of mixed ILC1, ILC2 and ILC3 transcriptional patterns, whereas, in contrast, the development of LTi cells did not go through multilineage priming. Our findings provide insight into the divergent mechanisms of the differentiation of the ILC lineage and LTi cell lineage and establish a high-resolution 'blueprint' of their development.
Asunto(s)
Linaje de la Célula/inmunología , Subgrupos Linfocitarios/inmunología , Linfocitos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Diferenciación Celular/genética , Citometría de Flujo , Perfilación de la Expresión Génica , Factor Nuclear 1-alfa del Hepatocito/inmunología , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/inmunología , Tejido Linfoide/citología , Ratones , Reacción en Cadena de la Polimerasa Multiplex , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de la Célula IndividualRESUMEN
The cross-talk between the microbiota and the immune system plays a fundamental role in the control of host physiology. However, the tissue-specific factors controlling this dialogue remain poorly understood. Here we demonstrate that T cell responses to commensal colonization are associated with the development of organized cellular clusters within the skin epithelium. These organized lymphocyte clusters are surrounded by keratinocytes expressing a discrete program associated with antigen presentation and antimicrobial defense. Notably, IL-22-mediated keratinocyte-intrinsic MHC class II expression was required for the selective accumulation of commensal-induced IFN-γ, but not IL-17A-producing CD4+ T cells within the skin. Taking these data together, this work uncovers an unexpected role for MHC class II expression by keratinocytes in the control of homeostatic type 1 responses to the microbiota. Our findings have important implications for the understanding of the tissue-specific rules governing the dialogue between a host and its microbiota.
Asunto(s)
Epidermis/microbiología , Antígenos de Histocompatibilidad Clase II/biosíntesis , Interacciones Microbiota-Huesped/inmunología , Queratinocitos/inmunología , Microbiota/inmunología , Células TH1/inmunología , Animales , Presentación de Antígeno , Candida albicans/inmunología , Epidermis/inmunología , Genes MHC Clase II , Interferón gamma/biosíntesis , Queratinocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos , Quimera por Radiación , Organismos Libres de Patógenos Específicos , Staphylococcus aureus/inmunología , Staphylococcus epidermidis/inmunología , Simbiosis , Células TH1/metabolismoRESUMEN
The thymus is critical for the establishment of the adaptive immune system and the development of a diverse T cell repertoire. T cell development depends upon cell-cell interactions with epithelial cells in the thymus. The thymus is composed of two different types of epithelial cells: cortical and medullary epithelial cells. Both of these express and critically depend on the transcription factor Foxn1 Foxn1 is also expressed in the hair follicle, and disruption of Foxn1 function in mice results in severe thymic developmental defects and the hairless (nude) phenotype. Despite its importance, little is known about the direct regulation of Foxn1 expression. In this study, we identify a cis-regulatory element (RE) critical for expression of Foxn1 in mouse thymic epithelial cells but dispensable for expression in hair follicles. Analysis of chromatin accessibility, histone modifications, and sequence conservation identified regions within the first intron of Foxn1 that possessed the characteristics of REs. Systematic knockout of candidate regions lead us to identify a 1.6 kb region that, when deleted, results in a near total disruption of thymus development. Interestingly, Foxn1 expression and function in the hair follicle were unaffected. RNA fluorescent in situ hybridization showed a near complete loss of Foxn1 mRNA expression in the embryonic thymic bud. Our studies have identified a genomic RE with thymic-specific control of Foxn1 gene expression.
Asunto(s)
Células Epiteliales/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Elementos Reguladores de la Transcripción/genética , Linfocitos T/inmunología , Timo/metabolismo , Animales , Factores de Transcripción Forkhead/biosíntesis , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Folículo Piloso/metabolismo , Ratones , Ratones Noqueados , Ratones Desnudos , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Linfocitos T/citología , Timo/citologíaRESUMEN
Innate lymphoid cells (ILCs) specialize in the rapid secretion of polarized sets of cytokines and chemokines to combat infection and promote tissue repair at mucosal barriers. Their diversity and similarities with previously characterized natural killer (NK) cells and lymphoid tissue inducers (LTi) have prompted a provisional classification of all innate lymphocytes into groups 1, 2 and 3 solely on the basis of cytokine properties, but their developmental pathways and lineage relationships remain elusive. Here we identify and characterize a novel subset of lymphoid precursors in mouse fetal liver and adult bone marrow that transiently express high amounts of PLZF, a transcription factor previously associated with NK T cell development, by using lineage tracing and transfer studies. PLZF(high) cells were committed ILC progenitors with multiple ILC1, ILC2 and ILC3 potential at the clonal level. They excluded classical LTi and NK cells, but included a peculiar subset of NK1.1(+)DX5(-) 'NK-like' cells residing in the liver. Deletion of PLZF markedly altered the development of several ILC subsets, but not LTi or NK cells. PLZF(high) precursors also expressed high amounts of ID2 and GATA3, as well as TOX, a known regulator of PLZF-independent NK and LTi lineages. These findings establish novel lineage relationships between ILC, NK and LTi cells, and identify the common precursor to ILCs, termed ILCP. They also reveal the broad, defining role of PLZF in the differentiation of innate lymphocytes.
Asunto(s)
Linaje de la Célula , Linfocitos/citología , Células Madre/citología , Animales , Células de la Médula Ósea/citología , Diferenciación Celular , Factor de Transcripción GATA3/metabolismo , Proteínas HMGB/metabolismo , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Células Asesinas Naturales/citología , Factores de Transcripción de Tipo Kruppel/metabolismo , Hígado/citología , Hígado/embriología , Ratones , Células T Asesinas Naturales/citología , Proteína de la Leucemia Promielocítica con Dedos de ZincRESUMEN
The transcription factor PLZF [promyelocytic leukemia zinc finger, encoded by zinc finger BTB domain containing 16 (Zbtb16)] is induced during the development of innate and innate-like lymphocytes to direct their acquisition of a T-helper effector program, but the molecular mechanisms involved are poorly understood. Using biotinylation-based ChIP-seq and microarray analysis of both natural killer T (NKT) cells and PLZF-transgenic thymocytes, we identified several layers of regulation of the innate-like NKT effector program. First, PLZF bound and regulated genes encoding cytokine receptors as well as homing and adhesion receptors; second, PLZF bound and activated T-helper-specific transcription factor genes that in turn control T-helper-specific programs; finally, PLZF bound and suppressed the transcription of Bach2, a potent general repressor of effector differentiation in naive T cells. These findings reveal the multilayered architecture of the transcriptional program recruited by PLZF and elucidate how a single transcription factor can drive the developmental acquisition of a broad effector program.
Asunto(s)
Regulación de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/metabolismo , Células T Asesinas Naturales/fisiología , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Subunidades alfa del Factor de Unión al Sitio Principal/metabolismo , Citocinas/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Proteínas Proto-Oncogénicas c-ets/metabolismo , Receptores de Quimiocina/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
The differentiation of several T- and B-cell effector programs in the immune system is directed by signature transcription factors that induce rapid epigenetic remodelling. Here we report that promyelocytic leukaemia zinc finger (PLZF), the BTB-zinc finger (BTB-ZF) transcription factor directing the innate-like effector program of natural killer T-cell thymocytes, is prominently associated with cullin 3 (CUL3), an E3 ubiquitin ligase previously shown to use BTB domain-containing proteins as adaptors for substrate binding. PLZF transports CUL3 to the nucleus, where the two proteins are associated within a chromatin-modifying complex. Furthermore, PLZF expression results in selective ubiquitination changes of several components of this complex. CUL3 was also found associated with the BTB-ZF transcription factor BCL6, which directs the germinal-centre B cell and follicular T-helper cell programs. Conditional CUL3 deletion in mice demonstrated an essential role for CUL3 in the development of PLZF- and BCL6-dependent lineages. We conclude that distinct lineage-specific BTB-ZF transcription factors recruit CUL3 to alter the ubiquitination pattern of their associated chromatin-modifying complex. We propose that this new function is essential to direct the differentiation of several T- and B-cell effector programs, and may also be involved in the oncogenic role of PLZF and BCL6 in leukaemias and lymphomas.
Asunto(s)
Linfocitos B/metabolismo , Proteínas Cullin/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Linfocitos T/metabolismo , Dedos de Zinc , Animales , Linfocitos B/citología , Diferenciación Celular , Línea Celular , Proteínas Cullin/química , Proteínas Cullin/genética , Proteínas de Unión al ADN/metabolismo , Ratones , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Unión Proteica , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-bcl-6 , Linfocitos T/citología , UbiquitinaciónRESUMEN
Among the variety of tissue-resident NK-like populations recently distinguished from recirculating classical NK (cNK) cells, liver innate lymphoid cells (ILC) type 1 (ILC1s) have been shown to represent a distinct lineage that originates from a novel promyelocytic leukaemia zinc finger (PLZF)-expressing ILC precursor (ILCP) strictly committed to the ILC1, ILC2, and ILC3 lineages. Here, using PLZF-reporter mice and cell transfer assays, we studied the developmental progression of ILC1s and demonstrated substantial overlap with stages previously ascribed to the cNK lineage, including pre-pro-NK, pre-NK precursor (pre-NKP), refined NKP (rNKP), and immature NK (iNK). Although they originated from different precursors, the ILC1 and cNK lineages followed a parallel progression at early stages and diverged later at the iNK stage, with a striking predominance of ILC1s over cNKs early in ontogeny. Although a limited set of ILC1 genes depended on PLZF for expression, characteristically including Il7r, most of these genes were also differentially expressed between ILC1s and cNKs, indicating that PLZF together with other, yet to be defined, factors contribute to the divergence between these lineages.
Asunto(s)
Linaje de la Célula , Inmunidad Innata , Factores de Transcripción de Tipo Kruppel/metabolismo , Linfocitos/citología , Linfocitos/metabolismo , Animales , Animales Recién Nacidos , Antígenos Ly/metabolismo , Células de la Médula Ósea/citología , Diferenciación Celular/genética , Linaje de la Célula/genética , Feto/citología , Perfilación de la Expresión Génica , Inmunidad Innata/genética , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Hígado/citología , Hígado/embriología , Ratones Endogámicos C57BL , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Células Madre/citología , Células Madre/inmunologíaRESUMEN
The transcriptional control of CD1d-restricted NKT cell development has remained elusive. We report that PLZF (promyelocytic leukemia zinc finger, Zbtb16), a member of the BTB/POZ-ZF family of transcription factors that includes the CD4-lineage-specific c-Krox (Th-POK), is exquisitely specific to CD1d-restricted NKT cells and human MR1-specific MAIT cells. PLZF was induced immediately after positive selection of NKT cell precursors, and PLZF-deficient NKT cells failed to undergo the intrathymic expansion and effector differentiation that characterize their lineage. Instead, they preserved a naive phenotype and were directed to lymph nodes. Conversely, transgenic expression of PLZF induced CD4(+) thymocytes to acquire effector differentiation and migrate to nonlymphoid tissues. We suggest that PLZF is a transcriptional signature of NKT cells that directs their innate-like effector differentiation during thymic development.
Asunto(s)
Factores de Transcripción de Tipo Kruppel/metabolismo , Linfocitos T/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Linaje de la Célula , Humanos , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos , Ratones Noqueados , Ratones Transgénicos , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Bazo/citología , Bazo/inmunología , Linfocitos T/citología , Linfocitos T/metabolismo , Timo/citología , Timo/inmunologíaRESUMEN
BACKGROUND: The transcription factor promyelocytic leukemia zinc finger (PLZF) is transiently expressed during development of type 2 innate lymphoid cells (ILC2s) but is not present at the mature stage. We hypothesized that PLZF-deficient ILC2s have functional defects in the innate allergic response and represent a tool for studying innate immunity in a mouse with a functional adaptive immune response. OBJECTIVE: We determined the consequences of PLZF deficiency on ILC2 function in response to innate and adaptive immune stimuli by using PLZF(-/-) mice and mixed wild-type:PLZF(-/-) bone marrow chimeras. METHODS: PLZF(-/-) mice, wild-type littermates, or mixed bone marrow chimeras were treated with the protease allergen papain or the cytokines IL-25 and IL-33 or infected with the helminth Nippostrongylus brasiliensis to induce innate type 2 allergic responses. Mice were sensitized with intraperitoneal ovalbumin-alum, followed by intranasal challenge with ovalbumin alone, to induce adaptive TH2 responses. Lungs were analyzed for immune cell subsets, and alveolar lavage fluid was analyzed for ILC2-derived cytokines. In addition, ILC2s were stimulated ex vivo for their capacity to release type 2 cytokines. RESULTS: PLZF-deficient lung ILC2s exhibit a cell-intrinsic defect in the secretion of IL-5 and IL-13 in response to innate stimuli, resulting in defective recruitment of eosinophils and goblet cell hyperplasia. In contrast, the adaptive allergic inflammatory response to ovalbumin and alum was unimpaired. CONCLUSIONS: PLZF expression at the innate lymphoid cell precursor stage has a long-range effect on the functional properties of mature ILC2s and highlights the importance of these cells for innate allergic responses in otherwise immunocompetent mice.
Asunto(s)
Hipersensibilidad/genética , Hipersensibilidad/inmunología , Inmunidad Innata/genética , Factores de Transcripción de Tipo Kruppel/genética , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Inmunidad Adaptativa/genética , Inmunidad Adaptativa/inmunología , Traslado Adoptivo , Alérgenos/inmunología , Animales , Antígenos de Superficie/metabolismo , Biomarcadores , Trasplante de Médula Ósea , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Helmintiasis/genética , Helmintiasis/inmunología , Helmintiasis/patología , Helmintos/inmunología , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/patología , Inmunofenotipificación , Interleucina-33/administración & dosificación , Interleucina-33/farmacología , Interleucinas/administración & dosificación , Interleucinas/farmacología , Factores de Transcripción de Tipo Kruppel/deficiencia , Activación de Linfocitos , Subgrupos Linfocitarios/efectos de los fármacos , Ratones , Ratones Noqueados , Ovalbúmina/inmunología , Papaína/administración & dosificación , Papaína/farmacología , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Eosinofilia Pulmonar/genética , Eosinofilia Pulmonar/inmunología , Eosinofilia Pulmonar/patología , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
α-Galactosylceramide represents a new class of vaccine adjuvants and immunomodulators that stimulate NKT cells to secrete Th1 and Th2 cytokines. Synthetic variants with short or unsaturated acyl chains exhibit a striking Th2 bias in vivo but no evidence of defect in TCR signaling or stimulation of NKT cells in vitro. Using cd1d1(fl/fl) mice, we demonstrated that distinct APC types explained the cytokine bias in vivo. Whereas NKT stimulation by α-Galactosylceramide required CD1d expression by dendritic cells (DCs), presentation of the Th2 variants was promiscuous and unaffected by DC-specific ablation of CD1d. This DC-independent stimulation failed to activate the feedback loop between DC IL-12 and NK cell IFN-γ, explaining the Th2 bias. Conversely, forced presentation of the Th2 variants by DC induced high IL-12. Thus, lipid structural variations that do not alter TCR recognition can activate distinct Th1 or Th2 cellular networks by changing APC targeting in vivo.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Galactosilceramidas/química , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Células T Asesinas Naturales/efectos de los fármacos , Animales , Presentación de Antígeno , Células Presentadoras de Antígenos/clasificación , Antígenos CD1d/biosíntesis , Antígenos CD1d/genética , Antígenos CD1d/inmunología , Linfocitos B/inmunología , Células Cultivadas/efectos de los fármacos , Células Cultivadas/inmunología , Células Cultivadas/metabolismo , Células Dendríticas/inmunología , Retroalimentación Fisiológica , Galactosilceramidas/inmunología , Galactosilceramidas/farmacología , Regulación de la Expresión Génica , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Organismos Libres de Patógenos Específicos , Relación Estructura-ActividadRESUMEN
Mucosal-associated invariant T (MAIT) cells are predominantly located in barrier tissues where they rapidly respond to pathogens and commensals by recognizing microbial derivatives of riboflavin synthesis. Early-life exposure to these metabolites imprints the abundance of MAIT cells within tissues, so we hypothesized that antibiotic use during this period may abrogate their development. We identified antibiotics that deplete riboflavin-synthesizing commensals and revealed an early period of susceptibility during which antibiotic administration impaired MAIT cell development. The reduction in MAIT cell abundance rendered mice more susceptible to pneumonia, while MAIT cell-deficient mice were unaffected by early-life antibiotics. Concomitant administration of a riboflavin-synthesizing commensal during antibiotic treatment was sufficient to restore MAIT cell development and immunity. Our work demonstrates that transient depletion of riboflavin-synthesizing commensals in early life can adversely affect responses to subsequent infections.
RESUMEN
Thymocytes expressing the NKT cell semi-invariant αß TCR are thought to undergo agonist interactions with CD1d ligands prior to expressing promyelocytic leukemia zinc finger (PLZF), a broad complex, tramtrack, bric-a-brac, poxvirus, and zinc finger transcription factor that directs acquisition of the effector program of these innate-like T cells. Whether PLZF can mediate this effector conversion independently of agonist signaling has not been investigated. We demonstrated that transgenic (Tg) expression of PLZF under the CD4 promoter induced the innate effector program in two different MHC class II-restricted TCR-Tg Rag1(-/-) models examined. In CD4 thymocytes expressing a fixed Tg TCR ß-chain, the associated TCRα sequences in wild-type and PLZF-Tg mice overlapped extensively, further demonstrating that PLZF could induce the effector program in most CD4 T cells that would normally be selected as naive cells. In contrast, PLZF altered the negative selection of thymocytes expressing TCR ß-chains reactive against several retroviral superantigens. Thus, PLZF is remarkable in that it is a transcription factor capable of inducing an effector program in the absence of T cell agonist interactions or cell division. Its expression may also enhance the survival of agonist-signaled thymocytes.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Factores de Transcripción de Tipo Kruppel/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos CD1d/genética , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/metabolismo , Linfocitos T CD4-Positivos/citología , Citometría de Flujo , Antígenos de Histocompatibilidad Clase II/inmunología , Factores de Transcripción de Tipo Kruppel/genética , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Ligandos , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Quimera por Radiación , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Transducción de Señal , Dedos de ZincRESUMEN
Rare CD1d-α-galactosylceramide-specific T cells that do not express the invariant Vα24 chain of human NKT cells were recently identified after expansion in vitro with the lipid Ag, but their phenotype and frequency in vivo and lineage relationship with NKT cells could not be elucidated. By using a CD1d tetramer-based method to enrich these cells from fresh peripheral blood, we demonstrated their naive-like CD62L(high)CD45RO(-)CD4(+) phenotype and relatively high frequency of â¼10(-5) in several healthy individuals. Notably, these cells expressed the NKT lineage-specific transcription promyelocytic leukemia zinc finger (PLZF), indicating a developmental relationship with NKT cells and ruling out the possibility that they were conventional MHC-restricted T cells cross-reacting against CD1d-α-galactosylceramide. Although PLZF is known to direct the effector program of NKT cells, we show in this study that the naive-like cells expressed it at a significantly lower amount than NKT cells. Further, we present mouse studies demonstrating a sharp PLZF expression threshold requirement for induction of the effector phenotype. These findings directly demonstrate in vivo the existence of naive-like CD1d-restricted human T cells marked by intermediate levels of PLZF.
Asunto(s)
Antígenos CD1d/fisiología , Factores de Transcripción de Tipo Kruppel/biosíntesis , Fase de Descanso del Ciclo Celular/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Adulto , Animales , Antígenos CD1d/sangre , Línea Celular Transformada , Células Clonales , Regulación de la Expresión Génica/inmunología , Humanos , Factores de Transcripción de Tipo Kruppel/sangre , Leucemia Promielocítica Aguda/inmunología , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Subgrupos de Linfocitos T/patología , Timo/citología , Timo/inmunología , Timo/metabolismo , Adulto Joven , Dedos de ZincRESUMEN
The pathogenicity of disease-associated microbes varies widely between individuals. In this issue of Cell Host & Microbe, Rice et al. demonstrate that interactions between intestinal commensals reciprocally modulate the host immune response to each microbe, ameliorating the inflammation caused by one and dampening antibody responses to the other.
Asunto(s)
Microbioma Gastrointestinal , Microbioma Gastrointestinal/fisiología , Humanos , Inflamación , Intestinos , SimbiosisRESUMEN
Unconventional T cellsincluding invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and defined subsets of γδ T cellsare restricted by monomorphic major histocompatibility complex class Ib (MHC-Ib) molecules and seed tissues during development. Early-life instructive signals, including those derived from the microbiota, establish homeostatic set points for unconventional T cells, a phenomenon that has lifelong consequences for the regulation of tissue immunity, inflammation, and repair. Unconventional T cells compete for niches within tissues, and recent evidence supports the idea that the fundamental role of these cells in tissue physiology may result from their action as a network with overlapping and potentially synergistic functions, rather than as individual subsets.