RESUMEN
Following immunization, lymph nodes dynamically expand and contract. The mechanical and cellular changes enabling the early-stage expansion of lymph nodes have been characterized, yet the durability of such responses and their implications for adaptive immunity and vaccine efficacy are unknown. Here, by leveraging high-frequency ultrasound imaging of the lymph nodes of mice, we report more potent and persistent lymph-node expansion for animals immunized with a mesoporous silica vaccine incorporating a model antigen than for animals given bolus immunization or standard vaccine formulations such as alum, and that durable and robust lymph-node expansion was associated with vaccine efficacy and adaptive immunity for 100 days post-vaccination in a mouse model of melanoma. Immunization altered the mechanical and extracellular-matrix properties of the lymph nodes, drove antigen-dependent proliferation of immune and stromal cells, and altered the transcriptional features of dendritic cells and inflammatory monocytes. Strategies that robustly maintain lymph-node expansion may result in enhanced vaccination outcomes.
RESUMEN
In this issue of Cell Reports Medicine, Qin et al.1 present a comprehensive single-cell transcriptomics analysis of the tumor microenvironment of rectal cancer tumors before and after neoadjuvant chemotherapy.
Asunto(s)
Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Estadificación de Neoplasias , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/patología , Microambiente TumoralRESUMEN
The cancer-immunity cycle provides a framework to understand the series of events that generate anti-cancer immune responses. It emphasizes the iterative nature of the response where the killing of tumor cells by T cells initiates subsequent rounds of antigen presentation and T cell stimulation, maintaining active immunity and adapting it to tumor evolution. Any step of the cycle can become rate-limiting, rendering the immune system unable to control tumor growth. Here, we update the cancer-immunity cycle based on the remarkable progress of the past decade. Understanding the mechanism of checkpoint inhibition has evolved, as has our view of dendritic cells in sustaining anti-tumor immunity. We additionally account for the role of the tumor microenvironment in facilitating, not just suppressing, the anti-cancer response, and discuss the importance of considering a tumor's immunological phenotype, the "immunotype". While these new insights add some complexity to the cycle, they also provide new targets for research and therapeutic intervention.
Asunto(s)
Inmunoterapia , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Linfocitos T , Presentación de Antígeno , Genotipo , Microambiente Tumoral/genéticaRESUMEN
TGFß signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFß signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFß and PD-L1 restrain intratumoral stem cell-like CD8 T cell (TSCL) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFß/PD-L1 blockade IFNγhi CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFß therapy efficacy. Our data suggest that TGFß works with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.
Asunto(s)
Antígeno B7-H1 , Neoplasias de la Mama , Linfocitos T CD8-positivos , Inhibidores de Puntos de Control Inmunológico , Factor de Crecimiento Transformador beta , Femenino , Animales , Ratones , Diferenciación Celular , Linfocitos T CD8-positivos/inmunología , Células Madre , Antígeno B7-H1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Interferón gamma/inmunología , Agotamiento de Células T , Inhibidores de Puntos de Control Inmunológico/farmacología , Ratones Endogámicos BALB C , Línea Celular Tumoral , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , RNA-SeqRESUMEN
The immune phenotype of a tumour is a key predictor of its response to immunotherapy1-4. Patients who respond to checkpoint blockade generally present with immune-inflamed5-7 tumours that are highly infiltrated by T cells. However, not all inflamed tumours respond to therapy, and even lower response rates occur among tumours that lack T cells (immune desert) or that spatially exclude T cells to the periphery of the tumour lesion (immune excluded)8. Despite the importance of these tumour immune phenotypes in patients, little is known about their development, heterogeneity or dynamics owing to the technical difficulty of tracking these features in situ. Here we introduce skin tumour array by microporation (STAMP)-a preclinical approach that combines high-throughput time-lapse imaging with next-generation sequencing of tumour arrays. Using STAMP, we followed the development of thousands of arrayed tumours in vivo to show that tumour immune phenotypes and outcomes vary between adjacent tumours and are controlled by local factors within the tumour microenvironment. Particularly, the recruitment of T cells by fibroblasts and monocytes into the tumour core was supportive of T cell cytotoxic activity and tumour rejection. Tumour immune phenotypes were dynamic over time and an early conversion to an immune-inflamed phenotype was predictive of spontaneous or therapy-induced tumour rejection. Thus, STAMP captures the dynamic relationships of the spatial, cellular and molecular components of tumour rejection and has the potential to translate therapeutic concepts into successful clinical strategies.
Asunto(s)
Neoplasias , Linfocitos T , Microambiente Tumoral , Humanos , Inmunoterapia , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Linfocitos T/inmunología , Fenotipo , Fibroblastos , Monocitos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
The lymph node (LN) is home to resident macrophage populations that are essential for immune function and homeostasis, but key factors controlling this niche are undefined. Here, we show that fibroblastic reticular cells (FRCs) are an essential component of the LN macrophage niche. Genetic ablation of FRCs caused rapid loss of macrophages and monocytes from LNs across two in vivo models. Macrophages co-localized with FRCs in human LNs, and murine single-cell RNA-sequencing revealed that FRC subsets broadly expressed master macrophage regulator CSF1. Functional assays containing purified FRCs and monocytes showed that CSF1R signaling was sufficient to support macrophage development. These effects were conserved between mouse and human systems. These data indicate an important role for FRCs in maintaining the LN parenchymal macrophage niche.
Asunto(s)
Fibroblastos , Transducción de Señal , Ratones , Humanos , Animales , Macrófagos , Ganglios LinfáticosRESUMEN
Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.
Asunto(s)
Antineoplásicos , Interleucina-6 , Neoplasias , Animales , Ratones , Antineoplásicos/uso terapéutico , Antígeno B7-H1/inmunología , Antígeno B7-H1/uso terapéutico , Linfocitos T CD8-positivos/metabolismo , Inmunoterapia , Interleucina-6/metabolismo , Neoplasias/inmunología , Neoplasias/terapiaRESUMEN
Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15)1-3. However, the molecular signals that underlie the development of LRRC15+ cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFß receptor type 2 signalling in healthy dermatopontin+ universal fibroblasts is essential for the development of cancer-associated LRRC15+ myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15-diphtheria toxin receptor knock-in mice to selectively deplete LRRC15+ CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8+ T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFß-dependent LRRC15+ CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8+ T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.
Asunto(s)
Fibroblastos Asociados al Cáncer , Proteínas de la Membrana , Miofibroblastos , Neoplasias Pancreáticas , Células del Estroma , Animales , Humanos , Ratones , Fibroblastos Asociados al Cáncer/metabolismo , Linfocitos T CD8-positivos/inmunología , Proteínas de la Membrana/metabolismo , Miofibroblastos/metabolismo , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Receptores de Factores de Crecimiento Transformadores beta , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral , Antígeno B7-H1RESUMEN
It is currently accepted that cancer-associated fibroblasts (CAF) participate in T-cell exclusion from tumor nests. To unbiasedly test this, we used single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors. We identified four main CAF populations, two of which are associated with T-cell exclusion: (i) MYH11+αSMA+ CAF, which are present in early-stage tumors and form a single cell layer lining cancer aggregates, and (ii) FAP+αSMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both populations orchestrate a particular structural tissue organization through dense and aligned fiber deposition compared with T cell-permissive CAF. Yet they produce distinct matrix molecules, including collagen IV (MYH11+αSMA+ CAF) and collagen XI/XII (FAP+αSMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T-cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell-excluded tumors. SIGNIFICANCE: The cellular and molecular programs driving T-cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T-cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to developing new strategies targeting T cell-excluding CAF. See related commentary by Sherman, p. 2501. This article is highlighted in the In This Issue feature, p. 2483.
Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias Pulmonares , Humanos , Fibroblastos Asociados al Cáncer/patología , Linfocitos T , Microambiente Tumoral , Inmunoterapia/métodos , Neoplasias Pulmonares/patología , FibroblastosRESUMEN
Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-ß in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-ß signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells. TGF-ß regulated the unique transcriptional program of the stem-like subset, including upregulation of inhibitory receptors specifically expressed on these cells. TGF-ß also promoted the terminal differentiation of exhausted CD8 T cells by suppressing the effector-associated program. Together, the absence of TGF-ß signaling resulted in significantly increased accumulation of effector-like CD8 T cells. These findings have implications for immunotherapies in general and especially for T cell therapy against chronic infections and cancer.
Asunto(s)
Coriomeningitis Linfocítica , Neoplasias , Animales , Linfocitos T CD8-positivos , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones , Infección Persistente , Receptor de Muerte Celular Programada 1 , Factor de Crecimiento Transformador betaRESUMEN
Recent studies have identified a unique cancer-associated fibroblast (CAF) population termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex class II molecules, suggesting a function in regulating tumor immunity. Here, by integrating multiple single-cell RNA-sequencing studies and performing robust lineage-tracing assays, we find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by downregulating mesothelial features and gaining fibroblastic features, a process induced by interleukin-1 and transforming growth factor ß. apCAFs directly ligate and induce naive CD4+ T cells into regulatory T cells (Tregs) in an antigen-specific manner. Moreover, treatment with an antibody targeting the mesothelial cell marker mesothelin can effectively inhibit mesothelial cell to apCAF transition and Treg formation induced by apCAFs. Taken together, our study elucidates how mesothelial cells may contribute to immune evasion in pancreatic cancer and provides insight on strategies to enhance cancer immune therapy.
Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias Pancreáticas , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos , Humanos , Neoplasias Pancreáticas/patología , Linfocitos T Reguladores , Factor de Crecimiento Transformador beta/metabolismo , Neoplasias PancreáticasRESUMEN
The cancer-associated fibroblast (CAF) marker podoplanin (PDPN) is generally correlated with poor clinical outcomes in cancer patients and thus represents a promising therapeutic target. Despite its biomedical relevance, basic aspects of PDPN biology such as its cellular functions and cell surface ligands remain poorly uncharacterized, thus challenging drug development. Here, we utilize a high throughput platform to elucidate the PDPN cell surface interactome, and uncover the neutrophil protein CD177 as a new binding partner. Quantitative proteomics analysis of the CAF phosphoproteome reveals a role for PDPN in cell signaling, growth and actomyosin contractility, among other processes. Moreover, cellular assays demonstrate that CD177 is a functional antagonist, recapitulating the phenotype observed in PDPN-deficient CAFs. In sum, starting from the unbiased elucidation of the PDPN co-receptome, our work provides insights into PDPN functions and reveals the PDPN/CD177 axis as a possible modulator of fibroblast physiology in the tumor microenvironment.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Fibroblastos Asociados al Cáncer/patología , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Isoantígenos/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores de Superficie Celular/metabolismo , Microambiente Tumoral , Apoptosis , Biomarcadores de Tumor/genética , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/metabolismo , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Humanos , Isoantígenos/genética , Glicoproteínas de Membrana/genética , Neutrófilos/inmunología , Neutrófilos/metabolismo , Pronóstico , Receptores de Superficie Celular/genética , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
Myeloid cells encounter stromal cells and their matrix determinants on a continual basis during their residence in any given organ. Here, we examined the impact of the collagen receptor LAIR1 on myeloid cell homeostasis and function. LAIR1 was highly expressed in the myeloid lineage and enriched in non-classical monocytes. Proteomic definition of the LAIR1 interactome identified stromal factor Colec12 as a high-affinity LAIR1 ligand. Proteomic profiling of LAIR1 signaling triggered by Collagen1 and Colec12 highlighted pathways associated with survival, proliferation, and differentiation. Lair1-/- mice had reduced frequencies of Ly6C- monocytes, which were associated with altered proliferation and apoptosis of non-classical monocytes from bone marrow and altered heterogeneity of interstitial macrophages in lung. Myeloid-specific LAIR1 deficiency promoted metastatic growth in a melanoma model and LAIR1 expression associated with improved clinical outcomes in human metastatic melanoma. Thus, monocytes and macrophages rely on LAIR1 sensing of stromal determinants for fitness and function, with relevance in homeostasis and disease.
Asunto(s)
Homeostasis/fisiología , Pulmón/metabolismo , Macrófagos Alveolares/metabolismo , Monocitos/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Apoptosis/fisiología , Médula Ósea/metabolismo , Médula Ósea/patología , Células COS , Diferenciación Celular/fisiología , Línea Celular , Línea Celular Tumoral , Linaje de la Célula/fisiología , Proliferación Celular/fisiología , Chlorocebus aethiops , Femenino , Humanos , Pulmón/patología , Macrófagos Alveolares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/patología , Células Mieloides/metabolismo , Células Mieloides/patología , Metástasis de la Neoplasia/patología , Proteómica/métodos , Transducción de Señal/fisiologíaRESUMEN
Fibroblasts, custodians of tissue architecture and function, are no longer considered a monolithic entity across tissues and disease indications. Recent advances in single-cell technologies provide an unrestricted, high-resolution view of fibroblast heterogeneity that exists within and across tissues. In this review, we summarize a compendium of single-cell transcriptomic studies and provide a comprehensive accounting of fibroblast subsets, many of which have been described to occupy specific niches in tissues at homeostatic and pathologic states. Understanding this heterogeneity is particularly important in the context of cancer, as the diverse cancer-associated fibroblast (CAF) phenotypes in the tumor microenvironment (TME) are directly impacted by the expression phenotypes of their predecessors. Relationships between these heterogeneous populations often accompany and influence response to therapy in cancer and fibrosis. We further highlight the importance of integrating single-cell studies to deduce common fibroblast phenotypes across disease states, which will facilitate the identification of common signaling pathways, gene regulatory programs, and cell surface markers that are going to advance drug discovery and targeting.
Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias , Biomarcadores , Fibroblastos , Humanos , Neoplasias/genética , Neoplasias/terapia , Microambiente TumoralRESUMEN
Fibroblasts are non-haematopoietic structural cells that define the architecture of organs, support the homeostasis of tissue-resident cells and have key roles in fibrosis, cancer, autoimmunity and wound healing1. Recent studies have described fibroblast heterogeneity within individual tissues1. However, the field lacks a characterization of fibroblasts at single-cell resolution across tissues in healthy and diseased organs. Here we constructed fibroblast atlases by integrating single-cell transcriptomic data from about 230,000 fibroblasts across 17 tissues, 50 datasets, 11 disease states and 2 species. Mouse fibroblast atlases and a DptIRESCreERT2 knock-in mouse identified two universal fibroblast transcriptional subtypes across tissues. Our analysis suggests that these cells can serve as a reservoir that can yield specialized fibroblasts across a broad range of steady-state tissues and activated fibroblasts in disease. Comparison to an atlas of human fibroblasts from perturbed states showed that fibroblast transcriptional states are conserved between mice and humans, including universal fibroblasts and activated phenotypes associated with pathogenicity in human cancer, fibrosis, arthritis and inflammation. In summary, a cross-species and pan-tissue approach to transcriptomics at single-cell resolution has identified key organizing principles of the fibroblast lineage in health and disease.
Asunto(s)
Fibroblastos/citología , Transcriptoma , Animales , Células Cultivadas , Enfermedad , Femenino , Fibroblastos/clasificación , Técnicas de Sustitución del Gen , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias , Especificidad de Órganos , Fenotipo , RNA-Seq , Análisis de la Célula Individual , Células del EstromaRESUMEN
Fibroblasts and macrophages are present in all tissues, and mounting evidence supports that these cells engage in direct communication to influence the overall tissue microenvironment and affect disease outcomes. Here, we review the current understanding of the molecular mechanisms that underlie fibroblast-macrophage interactions in health, fibrosis, and cancer. We present an integrated view of fibroblast-macrophage interactions that is centered on the CSF1-CSF1R axis and discuss how additional molecular programs linking these cell types can underpin disease onset, progression, and resolution. These programs may be tissue and context dependent, affected also by macrophage and fibroblast origin and state, as seen most clearly in cancer. Continued efforts to understand these cells and the means by which they interact may provide therapeutic approaches for the treatment of fibrosis and cancer.
Asunto(s)
Fibroblastos/metabolismo , Fibrosis/metabolismo , Macrófagos/metabolismo , Neoplasias/metabolismo , Animales , Diferenciación Celular/fisiología , Humanos , Factor Estimulante de Colonias de Macrófagos/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Microambiente Tumoral/fisiologíaRESUMEN
Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies.
Asunto(s)
Biomarcadores de Tumor/genética , Fibroblastos/inmunología , Neoplasias Ováricas/inmunología , Análisis de la Célula Individual/métodos , Células del Estroma/inmunología , Linfocitos T/inmunología , Microambiente Tumoral , Biomarcadores de Tumor/inmunología , Quimiocina CXCL12/genética , Quimiocina CXCL12/inmunología , Quimiocina CXCL16/genética , Quimiocina CXCL16/inmunología , Quimiocinas CXC/genética , Quimiocinas CXC/inmunología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , RNA-Seq , Receptores CXCR4/genética , Receptores CXCR4/inmunología , Receptores CXCR6/genética , Receptores CXCR6/inmunología , Células del Estroma/metabolismo , Células del Estroma/patología , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
Repair of the intestinal epithelium is tightly regulated to maintain homeostasis. The response after epithelial damage needs to be local and proportional to the insult. How different types of damage are coupled to repair remains incompletely understood. We report that after distinct types of intestinal epithelial damage, IL-1R1 signaling in GREM1+ mesenchymal cells increases production of R-spondin 3 (RSPO3), a Wnt agonist required for intestinal stem cell self-renewal. In parallel, IL-1R1 signaling regulates IL-22 production by innate lymphoid cells and promotes epithelial hyperplasia and regeneration. Although the regulation of both RSPO3 and IL-22 is critical for epithelial recovery from Citrobacter rodentium infection, IL-1R1-dependent RSPO3 production by GREM1+ mesenchymal cells alone is sufficient and required for recovery after dextran sulfate sodium-induced colitis. These data demonstrate how IL-1R1-dependent signaling orchestrates distinct repair programs tailored to the type of injury sustained that are required to restore intestinal epithelial barrier function.
Asunto(s)
Citrobacter rodentium , Infecciones por Enterobacteriaceae/inmunología , Mucosa Intestinal/fisiología , Receptores Tipo I de Interleucina-1/inmunología , Animales , Células Cultivadas , Técnicas de Cocultivo , Colitis/inducido químicamente , Colitis/inmunología , Colitis/patología , Colon/efectos de los fármacos , Colon/inmunología , Colon/patología , Sulfato de Dextran , Células Epiteliales , Fibroblastos , Interleucinas/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Ratones Transgénicos , Organoides , Receptores Tipo I de Interleucina-1/genética , Regeneración , Transducción de Señal , Trombospondinas/inmunología , Interleucina-22RESUMEN
Fibroblastic reticular cells (FRCs) are specialized stromal cells that define tissue architecture and regulate lymphocyte compartmentalization, homeostasis, and innate and adaptive immunity in secondary lymphoid organs (SLOs). In the present study, we used single-cell RNA sequencing (scRNA-seq) of human and mouse lymph nodes (LNs) to identify a subset of T cell-zone FRCs defined by the expression of Gremlin1 (Grem1) in both species. Grem1-CreERT2 knock-in mice enabled localization, multi-omics characterization and genetic depletion of Grem1+ FRCs. Grem1+ FRCs primarily localize at T-B cell junctions of SLOs, neighboring pre-dendritic cells and conventional dendritic cells (cDCs). As such, their depletion resulted in preferential loss and decreased homeostatic proliferation and survival of resident cDCs and compromised T cell immunity. Trajectory analysis of human LN scRNA-seq data revealed expression similarities to murine FRCs, with GREM1+ cells marking the endpoint of both trajectories. These findings illuminate a new Grem1+ fibroblastic niche in LNs that functions to maintain the homeostasis of lymphoid tissue-resident cDCs.