RESUMEN
To understand the role of T cells in the pathogenesis of ulcerative colitis (UC), we analyzed colonic T cells isolated from patients with UC and controls. Here we identified colonic CD4+ and CD8+ T lymphocyte subsets with gene expression profiles resembling stem-like progenitors, previously reported in several mouse models of autoimmune disease. Stem-like T cells were increased in inflamed areas compared to non-inflamed regions from the same patients. Furthermore, TCR sequence analysis indicated stem-like T cells were clonally related to proinflammatory T cells, suggesting their involvement in sustaining effectors that drive inflammation. Using an adoptive transfer colitis model in mice, we demonstrated that CD4+ T cells deficient in either BCL-6 or TCF1, transcription factors that promote T cell stemness, had decreased colon T cells and diminished pathogenicity. Our results establish a strong association between stem-like T cell populations and UC pathogenesis, highlighting the potential of targeting this population to improve clinical outcomes.
Asunto(s)
Colitis Ulcerosa , Factor Nuclear 1-alfa del Hepatocito , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Humanos , Animales , Ratones , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD4-Positivos/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Células Madre/inmunología , Células Madre/metabolismo , Femenino , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Ratones Noqueados , Colon/inmunología , Colon/patología , Masculino , Ratones Endogámicos C57BL , Traslado Adoptivo , Modelos Animales de Enfermedad , Adulto , Persona de Mediana EdadRESUMEN
CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.
Asunto(s)
Adenocarcinoma del Pulmón/inmunología , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Neoplasias Pulmonares/inmunología , Células Madre/inmunología , Secuencia de Aminoácidos , Animales , Antígeno CTLA-4/metabolismo , Epítopos , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/patología , Ratones , Péptidos/química , Fenotipo , Receptor de Muerte Celular Programada 1/metabolismo , RNA-Seq , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores CCR6/metabolismo , Análisis de la Célula Individual , VacunaciónRESUMEN
Mesenchymal stem cells (MSCs) are self-renewing precursor cells that can differentiate into bone, fat, cartilage, and stromal cells of the bone marrow. Recent studies suggest that MSCs themselves are critical for forming a niche that maintains hematopoietic stem cells (HSCs). The ease by which human MSC-like and stromal progenitor cells can be isolated from the bone marrow and other tissues has led to the rapid development of clinical investigations exploring their anti-inflammatory properties, tissue preservation capabilities, and regenerative potential. However, the identity of genuine MSCs and their specific contributions to these various beneficial effects have remained enigmatic. In this article, we examine the definition of MSCs and discuss the importance of rigorously characterizing their stem cell activity. We review their role and that of other putative niche constituents in the regulation of bone marrow HSCs. Additionally, how MSCs and their stromal progeny alter immune function is discussed, as well as potential therapeutic implications.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Mesenquimatosas/métodos , Medicina Regenerativa/métodos , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Inflamación/terapia , Células Madre/inmunología , Células del Estroma/inmunología , Células del Estroma/patología , Células del Estroma/trasplanteRESUMEN
Stem cells heal wounds. In this issue of Immunity, Luan et al. demonstrate that epidermal stem cells orchestrate the recruitment of regulatory T (Treg) cells and neutrophils during wound healing. Treg cells facilitate a tolerogenic environment to protect epithelial regeneration while neutrophils promote inflammation to ward off infection.
Asunto(s)
Neutrófilos , Células Madre , Linfocitos T Reguladores , Cicatrización de Heridas , Cicatrización de Heridas/inmunología , Humanos , Células Madre/inmunología , Linfocitos T Reguladores/inmunología , Animales , Neutrófilos/inmunologíaRESUMEN
Conventional dendritic cells (cDC) are antigen-presenting cells comprising cDC1 and cDC2, responsible for priming naive CD8+ and CD4+ T cells, respectively. Recent studies have unveiled cDC2 heterogeneity and identified various cDC2 progenitors beyond the common DC progenitor (CDP), hinting at distinct cDC2 lineages. By generating Cd300ciCre-hCD2R26tdTomato reporter mice, we identified a bone marrow pro-cDC2 progenitor exclusively generating cDC2 in vitro and in vivo. Single-cell analyses and multiparametric flow cytometry demonstrated that pro-cDC2 encompasses myeloid-derived pre-cDC2 and lymphoid-derived plasmacytoid DC (pDC)-like precursors differentiating into a transcriptionally convergent cDC2 phenotype. Cd300c-traced cDC2 had distinct transcriptomic profiles, phenotypes, and tissue distributions compared with Ms4a3CreR26tdTomato lineage-traced DC3, a monocyte-DC progenitor (MDP)-derived subset that bypasses CDP. Mice with reduced Cd300c-traced cDC2 showed impaired humoral responses to T cell-dependent antigens. We conclude that progenitors of distinct lineages shape the diversity of mature cDC2 across tissues. Thus, ontogenesis may impact tissue immune responses.
Asunto(s)
Diferenciación Celular , Linaje de la Célula , Células Dendríticas , Animales , Células Dendríticas/inmunología , Ratones , Diferenciación Celular/inmunología , Ratones Endogámicos C57BL , Análisis de la Célula Individual , Células Madre/citología , Células Madre/inmunología , Células Madre/metabolismo , Ratones TransgénicosRESUMEN
Following tissue damage, epithelial stem cells (SCs) are mobilized to enter the wound, where they confront harsh inflammatory environments that can impede their ability to repair the injury. Here, we investigated the mechanisms that protect skin SCs within this inflammatory environment. Characterization of gene expression profiles of hair follicle SCs (HFSCs) that migrated into the wound site revealed activation of an immune-modulatory program, including expression of CD80, major histocompatibility complex class II (MHCII), and CXC motif chemokine ligand 5 (CXCL5). Deletion of CD80 in HFSCs impaired re-epithelialization, reduced accumulation of peripherally generated Treg (pTreg) cells, and increased infiltration of neutrophils in wounded skin. Importantly, similar wound healing defects were also observed in mice lacking pTreg cells. Our findings suggest that upon skin injury, HFSCs establish a temporary protective network by promoting local expansion of Treg cells, thereby enabling re-epithelialization while still kindling inflammation outside this niche until the barrier is restored.
Asunto(s)
Antígeno B7-1 , Folículo Piloso , Inflamación , Piel , Células Madre , Linfocitos T Reguladores , Cicatrización de Heridas , Animales , Linfocitos T Reguladores/inmunología , Ratones , Cicatrización de Heridas/inmunología , Piel/inmunología , Piel/lesiones , Piel/patología , Células Madre/inmunología , Células Madre/metabolismo , Inflamación/inmunología , Folículo Piloso/inmunología , Antígeno B7-1/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Repitelización/inmunología , Movimiento Celular/inmunología , Proliferación CelularRESUMEN
Stem cells regenerate tissues in homeostasis and under stress. By taking cues from their microenvironment or "niche," they smoothly transition between these states. Immune cells have surfaced as prominent members of stem cell niches across the body. Here, we draw parallels between different stem cell niches to explore the context-specific interactions that stem cells have with tissue-resident and recruited immune cells. We also highlight stem cells' innate ability to sense and respond to stress and the enduring memory that forms from such encounters. This fascinating crosstalk holds great promise for novel therapies in inflammatory diseases and regenerative medicine.
Asunto(s)
Células Madre/inmunología , Animales , Homeostasis , Humanos , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/patología , Nicho de Células Madre/inmunologíaRESUMEN
Stem cells are maintained by transcriptional programs that promote self-renewal and repress differentiation. Here, we found that the transcription factor c-Myb was essential for generating and maintaining stem cells in the CD8+ T cell memory compartment. Following viral infection, CD8+ T cells lacking Myb underwent terminal differentiation and generated fewer stem cell-like central memory cells than did Myb-sufficient T cells. c-Myb acted both as a transcriptional activator of Tcf7 (which encodes the transcription factor Tcf1) to enhance memory development and as a repressor of Zeb2 (which encodes the transcription factor Zeb2) to hinder effector differentiation. Domain-mutagenesis experiments revealed that the transactivation domain of c-Myb was necessary for restraining differentiation, whereas its negative regulatory domain was critical for cell survival. Myb overexpression enhanced CD8+ T cell memory formation, polyfunctionality and recall responses that promoted curative antitumor immunity after adoptive transfer. These findings identify c-Myb as a pivotal regulator of CD8+ T cell stemness and highlight its therapeutic potential.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Neoplasias Experimentales/inmunología , Proteínas Proto-Oncogénicas c-myb/inmunología , Células Madre/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Diferenciación Celular/inmunología , Línea Celular Tumoral , Células HEK293 , Humanos , Memoria Inmunológica/genética , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/metabolismo , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/virología , Proteínas Proto-Oncogénicas c-myb/genética , Proteínas Proto-Oncogénicas c-myb/metabolismo , Células Madre/metabolismo , Células Madre/virología , Factor 1 de Transcripción de Linfocitos T/genética , Factor 1 de Transcripción de Linfocitos T/inmunología , Factor 1 de Transcripción de Linfocitos T/metabolismoRESUMEN
Plasmacytoid dendritic cells (pDCs) are an immune subset devoted to the production of high amounts of type 1 interferons in response to viral infections. Whereas conventional dendritic cells (cDCs) originate mostly from a common dendritic cell progenitor (CDP), pDCs have been shown to develop from both CDPs and common lymphoid progenitors. Here, we found that pDCs developed predominantly from IL-7R+ lymphoid progenitor cells. Expression of SiglecH and Ly6D defined pDC lineage commitment along the lymphoid branch. Transcriptional characterization of SiglecH+Ly6D+ precursors indicated that pDC development requires high expression of the transcription factor IRF8, whereas pDC identity relies on TCF4. RNA sequencing of IL-7R+ lymphoid and CDP-derived pDCs mirrored the heterogeneity of mature pDCs observed in single-cell analysis. Both mature pDC subsets are able to secrete type 1 interferons, but only myeloid-derived pDCs share with cDCs their ability to process and present antigen.
Asunto(s)
Células Dendríticas/inmunología , Células Madre/inmunología , Animales , Linfocitos B/citología , Linaje de la Célula , Células Cultivadas , Células Dendríticas/citología , Femenino , Proteínas Activadoras de GTPasa/metabolismo , Factores Reguladores del Interferón/metabolismo , Lectinas/metabolismo , Masculino , Ratones , Receptores de Superficie Celular/metabolismo , Receptores de Interleucina-7/metabolismo , Transactivadores/metabolismo , Transcripción GenéticaRESUMEN
Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1-4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass6-8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.
Asunto(s)
Proteína Forkhead Box O1 , Inmunoterapia Adoptiva , Neoplasias , Receptores Quiméricos de Antígenos , Células Madre , Linfocitos T , Humanos , Ratones , Línea Celular Tumoral , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Mitocondrias/metabolismo , Fenotipo , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/citología , Microambiente Tumoral/inmunología , Células Madre/citología , Células Madre/inmunología , Células Madre/metabolismo , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapiaRESUMEN
Cancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5-9 can promote anticancer responses through TCF1+ stem-like CD8+ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1+CD8+ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ T cells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes. PGE2 acts through EP2 and EP4 (EP2/EP4) receptor signalling in CD8+ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1+ tumour-infiltrating CD8+ T lymphocytes (TILs). Ablation of EP2/EP4 signalling in cancer-specific CD8+ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE2-mediated inhibition of TCF1+ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1+ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE2-EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.
Asunto(s)
Linfocitos T CD8-positivos , Proliferación Celular , Dinoprostona , Linfocitos Infiltrantes de Tumor , Neoplasias , Células Madre , Escape del Tumor , Animales , Femenino , Humanos , Masculino , Ratones , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Interleucina-2 , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones Endogámicos C57BL , Neoplasias/inmunología , Neoplasias/prevención & control , Subtipo EP2 de Receptores de Prostaglandina E/deficiencia , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/deficiencia , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Transducción de Señal , Células Madre/citología , Células Madre/inmunología , Células Madre/metabolismo , Escape del Tumor/inmunologíaRESUMEN
Lymphoid tissue inducer (LTi) cells are regarded as a subset of innate lymphoid cells (ILCs). However, these cells are not derived from the ILC common progenitor, which generates other ILC subsets and is defined by the expression of the transcription factor PLZF. Here, we examined transcription factor(s) determining the fate of LTi progenitors versus non-LTi ILC progenitors. Conditional deletion of Gata3 resulted in the loss of PLZF+ non-LTi progenitors but not the LTi progenitors that expressed the transcription factor RORγt. Consistently, PLZF+ non-LTi progenitors expressed high amounts of GATA3, whereas GATA3 expression was low in RORγt+ LTi progenitors. The generation of both progenitors required the transcriptional regulator Id2, which defines the common helper-like innate lymphoid progenitor (ChILP), but not cytokine signaling. Nevertheless, low GATA3 expression was necessary for the generation of functionally mature LTi cells. Thus, differential expression of GATA3 determines the fates and functions of distinct ILC progenitors.
Asunto(s)
Factor de Transcripción GATA3/biosíntesis , Células Madre/citología , Subgrupos de Linfocitos T/citología , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Linaje de la Célula/inmunología , Células Cultivadas , Factor de Transcripción GATA3/genética , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Subunidad gamma Común de Receptores de Interleucina/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/biosíntesis , Receptor de Muerte Celular Programada 1/biosíntesis , Proteína de la Leucemia Promielocítica con Dedos de Zinc/biosíntesis , Células Madre/inmunología , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Checkpoint blockade mediates a proliferative response of tumor-infiltrating CD8+ T lymphocytes (TILs). The origin of this response has remained elusive because chronic activation promotes terminal differentiation or exhaustion of tumor-specific T cells. Here we identified a subset of tumor-reactive TILs bearing hallmarks of exhausted cells and central memory cells, including expression of the checkpoint protein PD-1 and the transcription factor Tcf1. Tcf1+PD-1+ TILs mediated the proliferative response to immunotherapy, generating both Tcf1+PD-1+ and differentiated Tcf1-PD-1+ cells. Ablation of Tcf1+PD-1+ TILs restricted responses to immunotherapy. Tcf1 was not required for the generation of Tcf1+PD-1+ TILs but was essential for the stem-like functions of these cells. Human TCF1+PD-1+ cells were detected among tumor-reactive CD8+ T cells in the blood of melanoma patients and among TILs of primary melanomas. Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Células Madre/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Diferenciación Celular , Proliferación Celular , Receptor 2 Celular del Virus de la Hepatitis A/antagonistas & inhibidores , Factor Nuclear 1-alfa del Hepatocito/genética , Humanos , Inmunoterapia , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Melanoma/inmunología , Melanoma Experimental , Ratones , Ratones Endogámicos C57BLRESUMEN
Although the fetal immune system is considered tolerogenic, preterm infants can suffer from severe intestinal inflammation, including necrotizing enterocolitis (NEC). Here, we demonstrate that human fetal intestines predominantly contain tumor necrosis factor-α (TNF-α)+CD4+CD69+ T effector memory (Tem) cells. Single-cell RNA sequencing of fetal intestinal CD4+ T cells showed a T helper 1 phenotype and expression of genes mediating epithelial growth and cell cycling. Organoid co-cultures revealed a dose-dependent, TNF-α-mediated effect of fetal intestinal CD4+ T cells on intestinal stem cell (ISC) development, in which low T cell numbers supported epithelial development, whereas high numbers abrogated ISC proliferation. CD4+ Tem cell frequencies were higher in inflamed intestines from preterm infants with NEC than in healthy infant intestines and showed enhanced TNF signaling. These findings reveal a distinct population of TNF-α-producing CD4+ T cells that promote mucosal development in fetal intestines but can also mediate inflammation upon preterm birth.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Feto/inmunología , Memoria Inmunológica/inmunología , Intestinos/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Linfocitos T CD4-Positivos/metabolismo , Células Epiteliales/citología , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Femenino , Feto/metabolismo , Humanos , Recién Nacido , Mucosa Intestinal/embriología , Mucosa Intestinal/crecimiento & desarrollo , Mucosa Intestinal/inmunología , Intestinos/embriología , Intestinos/crecimiento & desarrollo , Ratones Endogámicos C57BL , Embarazo , Células Madre/citología , Células Madre/inmunología , Células Madre/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
CD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells1. How autoimmune T cell populations arise and are sustained, and the molecular programmes defining the autoimmune T cell state, are unknown. In type 1 diabetes, ß-cell-specific CD8 T cells destroy insulin-producing ß-cells. Here we followed the fate of ß-cell-specific CD8 T cells in non-obese diabetic mice throughout the course of type 1 diabetes. We identified a stem-like autoimmune progenitor population in the pancreatic draining lymph node (pLN), which self-renews and gives rise to pLN autoimmune mediators. pLN autoimmune mediators migrate to the pancreas, where they differentiate further and destroy ß-cells. Whereas transplantation of as few as 20 autoimmune progenitors induced type 1 diabetes, as many as 100,000 pancreatic autoimmune mediators did not. Pancreatic autoimmune mediators are short-lived, and stem-like autoimmune progenitors must continuously seed the pancreas to sustain ß-cell destruction. Single-cell RNA sequencing and clonal analysis revealed that autoimmune CD8 T cells represent unique T cell differentiation states and identified features driving the transition from autoimmune progenitor to autoimmune mediator. Strategies aimed at targeting the stem-like autoimmune progenitor pool could emerge as novel and powerful immunotherapeutic interventions for type 1 diabetes.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Células Secretoras de Insulina/inmunología , Células Madre/patología , Animales , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/trasplante , Autorrenovación de las Células , Células Clonales/inmunología , Células Clonales/metabolismo , Células Clonales/patología , Modelos Animales de Enfermedad , Femenino , Glucosa-6-Fosfatasa/inmunología , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Células Secretoras de Insulina/patología , Ganglios Linfáticos/inmunología , Masculino , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Análisis de la Célula Individual , Trasplante de Células Madre , Células Madre/inmunología , Células Madre/metabolismo , TranscriptomaRESUMEN
The transcription factors Batf3 and IRF8 are required for the development of CD8α(+) conventional dendritic cells (cDCs), but the basis for their actions has remained unclear. Here we identified two progenitor cells positive for the transcription factor Zbtb46 that separately generated CD8α(+) cDCs and CD4(+) cDCs and arose directly from the common DC progenitor (CDP). Irf8 expression in CDPs required prior autoactivation of Irf8 that was dependent on the transcription factor PU.1. Specification of the clonogenic progenitor of CD8α(+) cDCs (the pre-CD8 DC) required IRF8 but not Batf3. However, after specification of pre-CD8 DCs, autoactivation of Irf8 became Batf3 dependent at a CD8α(+) cDC-specific enhancer with multiple transcription factor AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3(-/-) mice that were specified toward development into pre-CD8 DCs failed to complete their development into CD8α(+) cDCs due to decay of Irf8 autoactivation and diverted to the CD4(+) cDC lineage.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Células Dendríticas/inmunología , Factores Reguladores del Interferón/inmunología , Proteínas Represoras/inmunología , Células Madre/inmunología , Animales , Secuencia de Bases , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Antígeno CD24/inmunología , Antígeno CD24/metabolismo , Antígenos CD8/inmunología , Antígenos CD8/metabolismo , Células Cultivadas , Células Clonales/inmunología , Células Clonales/metabolismo , Células Dendríticas/metabolismo , Citometría de Flujo , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Datos de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Unión Proteica , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Homología de Secuencia de Ácido Nucleico , Células Madre/metabolismo , Transcriptoma/genética , Transcriptoma/inmunologíaRESUMEN
Mouse conventional dendritic cells (cDCs) can be classified into two functionally distinct lineages: the CD8α(+) (CD103(+)) cDC1 lineage, and the CD11b(+) cDC2 lineage. cDCs arise from a cascade of bone marrow (BM) DC-committed progenitor cells that include the common DC progenitors (CDPs) and pre-DCs, which exit the BM and seed peripheral tissues before differentiating locally into mature cDCs. Where and when commitment to the cDC1 or cDC2 lineage occurs remains poorly understood. Here we found that transcriptional signatures of the cDC1 and cDC2 lineages became evident at the single-cell level from the CDP stage. We also identified Siglec-H and Ly6C as lineage markers that distinguished pre-DC subpopulations committed to the cDC1 lineage (Siglec-H(-)Ly6C(-) pre-DCs) or cDC2 lineage (Siglec-H(-)Ly6C(+) pre-DCs). Our results indicate that commitment to the cDC1 or cDC2 lineage occurs in the BM and not in the periphery.
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Células de la Médula Ósea/inmunología , Linaje de la Célula/inmunología , Células Dendríticas/inmunología , Células Madre/inmunología , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígenos Ly/genética , Antígenos Ly/inmunología , Antígenos Ly/metabolismo , Células de la Médula Ósea/metabolismo , Antígeno CD11b/inmunología , Antígeno CD11b/metabolismo , Antígenos CD8/inmunología , Antígenos CD8/metabolismo , Linaje de la Célula/genética , Células Cultivadas , Análisis por Conglomerados , Células Dendríticas/metabolismo , Células Dendríticas/ultraestructura , Citometría de Flujo , Cadenas alfa de Integrinas/inmunología , Cadenas alfa de Integrinas/metabolismo , Lectinas/genética , Lectinas/inmunología , Lectinas/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Electrónica de Rastreo , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Receptores de Superficie Celular/metabolismo , Análisis de la Célula Individual/métodos , Células Madre/metabolismo , Transcriptoma/genética , Transcriptoma/inmunologíaRESUMEN
Stem cells are critical for the maintenance of many tissues, but whether their integrity is maintained in the face of immunity is unclear. Here we found that cycling epithelial stem cells, including Lgr5+ intestinal stem cells, as well as ovary and mammary stem cells, were eliminated by activated T cells, but quiescent stem cells in the hair follicle and muscle were resistant to T cell killing. Immune evasion was an intrinsic property of the quiescent stem cells resulting from systemic downregulation of the antigen presentation machinery, including MHC class I and TAP proteins, and is mediated by the transactivator NLRC5. This process was reversed upon stem cell entry into the cell cycle. These studies identify a link between stem cell quiescence, antigen presentation, and immune evasion. As cancer-initiating cells can derive from stem cells, these findings may help explain how the earliest cancer cells evade immune surveillance.
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Folículo Piloso/citología , Evasión Inmune , Vigilancia Inmunológica , Células Madre/inmunología , Animales , Presentación de Antígeno , Péptidos y Proteínas de Señalización Intracelular/fisiología , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos C57BL , Músculos/citología , Receptores Acoplados a Proteínas G/fisiología , Escape del TumorRESUMEN
T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer1,2. Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1+ CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1+ stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1+TCF-1+ stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1+TCF-1+CD45RO+ stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth.