RESUMEN
BACKGROUND: Tissue-resident memory CD103+CD8+ T cells (CD103+CD8+ TRMs) are important components of anti-tumor immunity. However, the significance of CD103+CD8+ TRMs in colorectal cancer (CRC) and their advantages remain unclear. METHODS: Clinical data and specimens were used to evaluate the significance of CD103+CD8+ TRMs in CRC. A mouse subcutaneous tumorigenesis model and colony-formation assay were conducted to evaluate the anti-tumor effects of CD103+CD8+ TRMs. Finally, the infiltration density and function of CD103+CD8+ TRMs in the tumors were evaluated using flow cytometry. RESULTS: In this study, we showed that highly infiltrated CD103+CD8+ TRMs were associated with earlier clinical stage and negative VEGF expression in CRC patients and predicted a favorable prognosis for CRC/CRC liver metastases patients. Interestingly, we also found that CD103+CD8+ TRMs may have predictive potential for whether CRC develops liver metastasis in CRC. In addition, we found a positive correlation between the ratio of the number of α-SMA+ vessels to the sum of the number of α-SMA+ and CD31+ vessels in CRC, and the infiltration level of CD103+CD8+ TRMs. In addition, anti-angiogenic therapy promoted infiltration of CD103+CD8+ TRMs and enhanced their ability to secrete interferon (IFN)-γ, thus further improving the anti-tumor effect. Moreover, in vivo experiments showed that compared with peripheral blood CD8+ T cells, CD103+CD8+ TRMs infused back into the body could also further promote CD8+ T cells to infiltrate the tumor, and they had a stronger ability to secrete IFN-γ, which resulted in better anti-tumor effects. CONCLUSION: We demonstrated that CD103+CD8+ TRMs have the potential for clinical applications and provide new ideas for combined anti-tumor therapeutic strategies, such as anti-tumor angiogenesis therapy and CAR-T combined immunotherapy.
Asunto(s)
Antígenos CD , Linfocitos T CD8-positivos , Neoplasias Colorrectales , Memoria Inmunológica , Cadenas alfa de Integrinas , Neoplasias Hepáticas , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Cadenas alfa de Integrinas/metabolismo , Cadenas alfa de Integrinas/inmunología , Animales , Humanos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Antígenos CD/metabolismo , Pronóstico , Femenino , Masculino , Biomarcadores de Tumor/metabolismo , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Persona de Mediana EdadRESUMEN
Tissue-resident immune cells play important roles in local tissue homeostasis and infection control. There is no information on the functional role of lung-resident CD3-NK1.1+CD69+CD103+ cells in intranasal Bacillus Calmette-Guérin (BCG)-vaccinated and/or Mycobacterium tuberculosis (Mtb)-infected mice. Therefore, we phenotypically and functionally characterized these cells in mice vaccinated intranasally with BCG. We found that intranasal BCG vaccination increased CD3-NK1.1+ cells with a tissue-resident phenotype (CD69+CD103+) in the lungs during the first 7 d after BCG vaccination. Three months post-BCG vaccination, Mtb infection induced the expansion of CD3-NK1.1+CD69+CD103+ (lung-resident) cells in the lung. Adoptive transfer of lung-resident CD3-NK1.1+CD69+CD103+ cells from the lungs of BCG-vaccinated mice to Mtb-infected naive mice resulted in a lower bacterial burden and reduced inflammation in the lungs. Our findings demonstrated that intranasal BCG vaccination induces the expansion of CD3-NK1.1+CD69+CD103+ (lung-resident) cells to provide protection against Mtb infection.
Asunto(s)
Antígenos CD , Vacuna BCG , Cadenas alfa de Integrinas , Pulmón , Mycobacterium tuberculosis , Animales , Vacuna BCG/inmunología , Ratones , Pulmón/inmunología , Mycobacterium tuberculosis/inmunología , Antígenos CD/inmunología , Cadenas alfa de Integrinas/inmunología , Ratones Endogámicos C57BL , Complejo CD3/inmunología , Lectinas Tipo C/inmunología , Tuberculosis/inmunología , Tuberculosis/prevención & control , Femenino , Vacunación , Traslado Adoptivo , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/prevención & control , Antígenos de Diferenciación de Linfocitos TRESUMEN
Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a heterogeneous disease characterized by local inflammation of the upper airway and sinus mucosa. T cell-mediated immune responses play irreplaceable roles in the pathogenesis of nasal polyps. CD161+ T cells have been implicated in the pathology of several diseases through cytokine production and cytotoxic activity. However, the immunological characteristics of CD161+ T cells in nasal mucosa are still not well understood, particularly in CRSwNPs. Our research revealed a notable enrichment of CD161+ T cells in nasal tissues compared to peripheral blood, with a significantly more infiltration of CD161+ T cells in CRSwNPs compared to control nasal samples. Phenotypical analysis found that CD161+ T cells predominantly co-expressed tissue-resident memory surface markers CD103, CD69, and CD45RO. CD161+CD103+ T cells demonstrated complicated effector functions, marked by elevated levels of PD-1, CTLA-4, IL-17, and IFN-γ and diminished expression of FoxP3 and CD25. Interestingly, despite CD161+ T cells was more abundant in polyp tissues compared to normal control tissues, and then further categorizing polyp samples into distinct groups based on clinical characteristics, only the recurrent CRSwNP group showed a significant reduction in CD161+CD8+ T cells compared to the primary CRSwNP group. This finding suggested the necessity for further research to comprehensively understand the underlying mechanisms and the broader significance of CD161+ T cells in the advancement and relapse of CRSwNPs.
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Antígenos CD , Cadenas alfa de Integrinas , Subfamilia B de Receptores Similares a Lectina de Células NK , Pólipos Nasales , Rinosinusitis , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antígenos CD/metabolismo , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/metabolismo , Antígenos de Diferenciación de Linfocitos T/inmunología , Enfermedad Crónica , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/inmunología , Cadenas alfa de Integrinas/metabolismo , Cadenas alfa de Integrinas/inmunología , Interferón gamma/metabolismo , Interferón gamma/inmunología , Interleucina-17/metabolismo , Interleucina-17/inmunología , Lectinas Tipo C , Mucosa Nasal/inmunología , Pólipos Nasales/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Rinosinusitis/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismoAsunto(s)
Antígenos CD , Cadenas alfa de Integrinas , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Cadenas alfa de Integrinas/metabolismo , Cadenas alfa de Integrinas/inmunología , Ratones , Citotoxicidad Inmunológica , Humanos , Linfocitos T CD8-positivos/inmunología , Sinapsis Inmunológicas/inmunología , Sinapsis Inmunológicas/metabolismoRESUMEN
NK cells have been shown to exhibit inflammatory and immunoregulatory functions in a variety of healthy and diseased settings. In the context of chronic viral infection and cancer, distinct NK cell populations that inhibit adaptive immune responses have been observed. To understand how these cells arise and further characterize their immunosuppressive role, we examined in vitro conditions that could polarize human NK cells into an inhibitory subset. TGF-ß1 has been shown to induce regulatory T cells in vitro and in vivo; we therefore investigated if TGF-ß1 could also induce immunosuppressive NK-like cells. First, we found that TGF-ß1/IL-15, but not IL-15 alone, induced CD103+CD49a+ NK-like cells from peripheral blood NK cells, which expressed markers previously associated with inhibitory CD56+ innate lymphoid cells, including high expression of GITR and CD101. Moreover, supernatant from ascites collected from patients with ovarian carcinoma also induced CD103+CD49a+ NK-like cells in vitro in a TGF-ß-dependent manner. Interestingly, TGF-ß1/IL-15-induced CD103+CD56+ NK-like cells suppressed autologous CD4+ T cells in vitro by reducing absolute number, proliferation, and expression of activation marker CD25. Collectively, these findings provide new insight into how NK cells may acquire an inhibitory phenotype in TGF-ß1-rich environments.
Asunto(s)
Interleucina-15 , Células Asesinas Naturales , Factor de Crecimiento Transformador beta1 , Humanos , Células Asesinas Naturales/inmunología , Interleucina-15/inmunología , Interleucina-15/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Femenino , Antígenos CD/metabolismo , Antígenos CD/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Cadenas alfa de Integrinas/metabolismo , Cadenas alfa de Integrinas/inmunología , Antígeno CD56/metabolismo , Células Cultivadas , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Activación de Linfocitos/inmunologíaRESUMEN
BACKGROUND & AIMS: Although the presence of tertiary lymphoid structures (TLS) correlates with positive responses to immunotherapy in many solid malignancies, the mechanism by which TLS enhances antitumor immunity is not well understood. The present study aimed to investigate the underlying cross talk circuits between B cells and tissue-resident memory T (Trm) cells within the TLS and to understand their role in the context of immunotherapy. METHODS: Immunostaining and H&E staining of TLS and chemokine (C-X-C motif) ligand 13 (CXCL13)+ cluster of differentiation (CD)103+CD8+ Trm cells were performed on tumor sections from patients with gastric cancer (GC). The mechanism of communication between B cells and CXCL13+CD103+CD8+ Trm cells was determined in vitro and in vivo. The effect of CXCL13+CD103+CD8+ Trm cells in suppressing tumor growth was evaluated through anti-programmed cell death protein (PD)-1 therapy. RESULTS: The presence of TLS and CXCL13+CD103+CD8+ Trm cells in tumor tissues favored a superior response to anti-PD-1 therapy in patients with GC. Additionally, our research identified that activated B cells enhanced CXCL13 and granzyme B secretion by CD103+CD8+ Trm cells. Mechanistically, B cells facilitated the glycolysis of CD103+CD8+ Trm cells through the lymphotoxin-α/tumor necrosis factor receptor 2 (TNFR2) axis, and the mechanistic target of rapamycin signaling pathway played a critical role in CD103+CD8+ Trm cells glycolysis during this process. Moreover, the presence of TLS and CXCL13+CD103+CD8+ Trm cells correlated with potent responsiveness to anti-PD-1 therapy in a TNFR2-dependent manner. CONCLUSIONS: This study further reveals a crucial role for cellular communication between TLS-associated B cell and CXCL13+CD103+CD8+ Trm cells in antitumor immunity, providing valuable insights into the potential use of the lymphotoxin-α/TNFR2 axis within CXCL13+CD103+CD8+ Trm cells for advancing immunotherapy strategies in GC.
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Antígenos CD , Linfocitos B , Linfocitos T CD8-positivos , Quimiocina CXCL13 , Inhibidores de Puntos de Control Inmunológico , Cadenas alfa de Integrinas , Células T de Memoria , Receptor de Muerte Celular Programada 1 , Neoplasias Gástricas , Estructuras Linfoides Terciarias , Quimiocina CXCL13/metabolismo , Humanos , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/efectos de los fármacos , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Neoplasias Gástricas/tratamiento farmacológico , Antígenos CD/metabolismo , Cadenas alfa de Integrinas/metabolismo , Cadenas alfa de Integrinas/inmunología , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Animales , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Granzimas/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Memoria Inmunológica , Transducción de Señal/inmunología , Microambiente Tumoral/inmunología , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ratones , Inmunoterapia/métodos , Línea Celular TumoralRESUMEN
The detection of tumor-specific T cells in solid tumors is integral to interrogate endogenous antitumor responses and to advance downstream therapeutic applications. Multiple biomarkers are reported to identify endogenous tumor-specific tumor-infiltrating lymphocytes (TILs), namely CD137, PD-1, CD103, and CD39; however, a direct comparison of these molecules has yet to be performed. We evaluated these biomarkers in primary human ovarian tumor samples using single-cell mass cytometry to compare their relative phenotypic profiles, and examined their response to autologous tumor cells ex vivo. PD-1+ , CD103+ , and CD39+ TILs all contain a CD137+ cell subset, while CD137+ TILs highly co-express the aforementioned markers. CD137+ TILs exhibit the highest expression of cytotoxic effector molecules compared to PD-1+ , CD103+ , or CD39+ TILs. Removal of CD137+ cells from PD-1+ , CD103+ , or CD39+ TILs diminish their IFN-γ secretion in response to autologous tumor cell stimulation, while CD137+ TILs maintain high HLA-dependent IFN-γ secretion. CD137+ TILs exhibited an exhausted phenotype but with CD28 co-expression, suggesting possible receptiveness to reinvigoration via immune checkpoint blockade. Together, our findings demonstrate that the antitumor abilities of PD-1+ , CD103+ , and CD39+ TILs are mainly derived from a subset of CD137-expressing TILs, implicating CD137 as a more selective biomarker for naturally occurring tumor-specific TILs.
Asunto(s)
Antígenos CD/inmunología , Apirasa/inmunología , Biomarcadores de Tumor/inmunología , Cadenas alfa de Integrinas/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Ováricas/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Femenino , Humanos , Interferón gamma/inmunologíaRESUMEN
BACKGROUND: Although FoxP3+ regulatory T (Treg) cells constitute a highly heterogeneous population, with different regulatory potential depending on the disease context, distinct subsets or phenotypes remain poorly defined. This hampers the development of immunotherapy for allergic and autoimmune disorders. The present study aimed at characterizing distinct FoxP3+ Treg subpopulations involved in the suppression of Th2-mediated allergic inflammation in the lung. METHODS: We used an established mouse model of allergic airway disease based on ovalbumin sensitization and challenge to analyze FoxP3+ Tregs during the induction and resolution of inflammation, and identify markers that distinguish their most suppressive phenotypes. We also developed a new knock-in mouse model (Foxp3cre Cd103dtr ) enabling the specific ablation of CD103+ FoxP3+ Tregs for functional studies. RESULTS: We found that during resolution of allergic airway inflammation in mice >50% of FoxP3+ Treg cells expressed the integrin CD103 which marks FoxP3+ Treg cells of high IL-10 production, increased expression of immunoregulatory molecules such as KLRG1, ICOS and CD127, and enhanced suppressive capacity for Th2-mediated inflammatory responses. CD103+ FoxP3+ Tregs were essential for keeping allergic inflammation under control as their specific depletion in Foxp3cre Cd103dtr mice lead to severe alveocapillary damage, eosinophilic pneumonia, and markedly reduced lifespan of the animals. Conversely, adoptive transfer of CD103+ FoxP3+ Tregs effectively treated disease, attenuating Th2 responses and allergic inflammation in an IL-10-dependent manner. CONCLUSIONS: Our study identifies a novel regulatory T-cell population, defined by CD103 expression, programmed to prevent exuberant type 2 inflammation and keep homeostasis in the respiratory tract under control. This has important therapeutic implications.
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Antígenos CD/inmunología , Hipersensibilidad , Cadenas alfa de Integrinas/inmunología , Linfocitos T Reguladores , Animales , Citocinas/metabolismo , Factores de Transcripción Forkhead/metabolismo , Humanos , Inflamación/metabolismo , Integrinas/metabolismo , Interleucina-10/metabolismo , Pulmón , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
Targeting antigens to dendritic cells represent a promising method for enhancing immune responses against specific antigens. However, many studies have focused on systemic delivery (intravenous or intraperitoneally) of targeted antigen, approaches that are not easily transferable to humans. Here we evaluate the efficacy of an influenza vaccine targeting Xcr1+ cDC1 administered by intranasal immunization. Intranasal delivery of antigen fused to the chemokine Xcl1, the ligand of Xcr1, resulted in specific uptake by lung CD103+ cDC1. Interestingly, intranasal immunization with influenza A/PR/8/34 haemagglutinin (HA) fused to Xcl1, formulated with poly(I:C), resulted in enhanced induction of antigen-specific IFNγ+ CD4+ and IFNγ+ CD8+ T cell responses in lung compared non-targeted anti-NIP-HA (αNIP-HA). Induction of antibody responses was, however, similar in Xcl1-HA and αNIP-HA immunized mice, but significantly higher than in mice immunized with monomeric HA. Both Xcl1-HA and αNIP-HA vaccines induced full protection when mice were challenged with a lethal dose of influenza PR8 virus, reflecting the strong induction of HA-specific antibodies. Our results demonstrate that i.n. delivery of Xcl1-HA is a promising vaccine strategy for enhancing T cell responses in addition to inducing strong antibody responses.
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Linfocitos T CD8-positivos/inmunología , Quimiocinas C/metabolismo , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Infecciones por Orthomyxoviridae/inmunología , Poli I-C/inmunología , Animales , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , Antígenos/inmunología , Antígenos CD/inmunología , Línea Celular , Células Dendríticas/inmunología , Perros , Femenino , Células HEK293 , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Humanos , Cadenas alfa de Integrinas/inmunología , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos BALB CRESUMEN
Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM cell function, durability and malleability. We find that unequal responsiveness to TGFß is a major driver of this diversity. Notably, dampened TGFß signaling results in CD103- TRM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFß-responsive CD103+ TRM counterparts. Furthermore, whereas CD103- TRM cells readily modified their phenotype upon relocation, CD103+ TRM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for TRM cell development, tissue adaptation of these cells confers discrete functional properties such that TRM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Plasticidad de la Célula/inmunología , Microambiente Celular/inmunología , Memoria Inmunológica/inmunología , Animales , Antígenos CD/inmunología , Linfocitos T CD8-positivos/citología , Femenino , Cadenas alfa de Integrinas/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/inmunología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
In the present study, we evaluated the anti-inflammatory properties of Lactiplantibacillus plantarum 22A-3 (LP22A3) and attempted to elucidate the underlying molecular mechanism. The oral administration of LP22A3 significantly inhibited body weight reduction and decreased colon shortening and colitis score in mice with dextran sulfate sodium (DSS)-induced colitis. It was demonstrated that the production of the active-form of TGF-ß tended to increase in both the intestinal epithelial cells (IECs) of the ileum and serum but not in the colon of non-DSS-treated mice by LP22A3. IL-10 level in serum was also elevated by LP22A3-treatment. The mRNA expression of TGF-ß, IL-10 and Foxp3 increased only in the small intestines of LP22A3-treated mice. Both the aldehyde dehydrogenase 1 family member A2 (Aldh1a2) mRNA expression and population of CD103+ dendritic cells (DCs) in the small intestine significantly increased in the LP22A3-treated group. LP22A3 induced TGF-ß secretion from the IECs of the small intestine with retinoic acid production probably through TLR2, resulting in an increase in CD103+ DCs and the Foxp3+ Treg population. Both cells secrete a high level of anti-inflammatory cytokines, TGF-ß and IL-10 contributing to the protective condition in the intestine and thus making it less susceptible to inflammation. This suggested that oral administration of LP22A-3 may be an alternative therapeutic strategy for IBD.
Asunto(s)
Colitis/tratamiento farmacológico , Colitis/inmunología , Células Dendríticas/inmunología , Células Epiteliales/inmunología , Lactobacillaceae/fisiología , Probióticos/administración & dosificación , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta1/inmunología , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Diferenciación Celular , Colitis/genética , Colitis/fisiopatología , Células Dendríticas/citología , Células Epiteliales/microbiología , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Humanos , Cadenas alfa de Integrinas/genética , Cadenas alfa de Integrinas/inmunología , Interleucina-10/genética , Interleucina-10/inmunología , Intestinos/inmunología , Intestinos/microbiología , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/citología , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
BACKGROUND: Tissue resident memory T cells (TRMs) persist long-term in peripheral tissues without recirculation, triggering an immediate protective inflammatory state upon the re-recognition of the antigen. Despite evidence incriminating the dysregulation of TRMs in autoimmune diseases, few studies have examined their expression in cutaneous lupus erythematosus (CLE). OBJECTIVES: We aimed to examine whether there are differences among TRM populations in CLE depending on different clinical conditions, such as the CLE subtype or association with systemic lupus erythematosus, and to determine the effect of type I interferon (IFN) on the development of TRMs in CLE. METHODS: CLE disease activity was evaluated using the Cutaneous Lupus Erythematosus Disease Area and Severity Index. The expression of the TRM markers CD69 and CD103 in CLE lesions was evaluated by immunofluorescence. Flow cytometry was performed on peripheral blood mononuclear cells after IFNα treatment. RESULTS: The number of TRMs expressing either CD69 or CD103 was significantly higher in CLE lesions than in control skin; however, it was not significantly different between discoid lupus erythematosus and subacute CLE, or dependent on the presence of concomitant systemic lupus. Lesional severity was not correlated with an increase in TRMs in CLE. IFNα treatment induced a conspicuous increase in CD69 expression in skin-homing T cells, more profoundly in CD4+ T cells than in CD8+ T cells. CONCLUSIONS: Skin TRMs, either CD69 or CD103-positive cells, showed increased levels in the lesional skin of CLE, and IFNα increased the expression of CD69 in T cells.
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Interferón-alfa/inmunología , Lupus Eritematoso Cutáneo/inmunología , Células T de Memoria/inmunología , Piel/inmunología , Adulto , Antígenos CD/biosíntesis , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Antígenos de Diferenciación de Linfocitos T/inmunología , Femenino , Humanos , Cadenas alfa de Integrinas/biosíntesis , Cadenas alfa de Integrinas/inmunología , Interferón-alfa/farmacología , Lectinas Tipo C/biosíntesis , Lectinas Tipo C/inmunología , Lupus Eritematoso Discoide/inmunología , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Microsatellite-stable (MSS) colorectal cancers are characterized by low mutation burden and limited immune-cell infiltration and thereby respond poorly to immunotherapy. Here, we report a case of metastatic MSS colorectal cancer with a robust anticancer immune response. The primary tumor was resected in 2012, and the patient received several cycles of chemotherapy until 2017. In 2018, the patient underwent a left hepatectomy to remove a new metastasis. Analysis of the metastatic tumor revealed a strong CD8+ T-cell response. A high frequency of CD8+ T cells coexpressed CD39 and CD103, a phenotype characteristic of tumor-reactive cells. Using whole-exome sequencing, we identified somatic mutations that generated peptides recognized by CD39+CD103+CD8+ T cells. The observed reactivity against the tumor was dominated by the response to a single mutation that emerged in the metastasis. Somatic mutations that were not immunogenic in the primary tumor led to robust CD8+ T-cell expansion later during disease progression. Our data suggest that the cytotoxic treatment regimen received by the patient might be responsible for this effect. Hence, the capacity of cytotoxic regimens to prime the immune system in colorectal cancer patients should be investigated further and might provide a rationale for combination with immunotherapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Hepáticas/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Antígenos CD/inmunología , Apirasa/inmunología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Hepatectomía , Humanos , Cadenas alfa de Integrinas/inmunología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Masculino , Persona de Mediana EdadRESUMEN
Gut microbiota and the immune system are in constant exchange shaping both host immunity and microbial communities. Here, improper immune regulation can cause inflammatory bowel disease (IBD) and colitis. Antibody therapies blocking signaling through the CD40-CD40L axis showed promising results as these molecules are deregulated in certain IBD patients. To better understand the mechanism, we used transgenic DC-LMP1/CD40 animals with a constitutive CD40-signal in CD11c+ cells, causing a lack of intestinal CD103+ dendritic cells (DCs) and failure to induce regulatory T (iTreg) cells. These mice rapidly develop spontaneous fatal colitis, accompanied by dysbiosis and increased inflammatory IL-17+IFN-γ+ Th17/Th1 and IFN-γ + Th1 cells. In the present study, we analyzed the impact of the microbiota on disease development and detected elevated IgA- and IgG-levels in sera from DC-LMP1/CD40 animals. Their serum antibodies specifically bound intestinal bacteria, and by proteome analysis, we identified a 60 kDa chaperonin GroEL (Hsp60) from Helicobacter hepaticus (Hh) as the main specific antigen targeted in the absence of iTregs. When re-derived to a different Hh-free specific-pathogen-free (SPF) microbiota, mice showed few signs of disease, normal microbiota, and no fatality. Upon recolonization of mice with Hh, the disease developed rapidly. Thus, the present work identifies GroEL/Hsp60 as a major Hh-antigen and its role in disease onset, progression, and outcome in this colitis model. Our results highlight the importance of CD103+ DC- and iTreg-mediated immune tolerance to specific pathobionts to maintain healthy intestinal balance.
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Chaperonina 60/inmunología , Colitis/microbiología , Helicobacter hepaticus/patogenicidad , Animales , Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/inmunología , Antígenos CD/inmunología , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular , Colitis/inmunología , Células Dendríticas/inmunología , Helicobacter hepaticus/inmunología , Cadenas alfa de Integrinas/inmunología , Intestinos/inmunología , Intestinos/microbiología , Ratones , Ratones Transgénicos , Organismos Libres de Patógenos Específicos , Linfocitos T Reguladores/inmunologíaRESUMEN
The theory of cancer immunoediting, which describes the dynamic interactions between tumors and host immune cells that shape the character of each compartment, is foundational for understanding cancer immunotherapy. Few models exist that facilitate in-depth study of each of the three canonical phases of immunoediting: elimination, equilibrium, and escape. Here, we utilized NPK-C1, a transplantable prostate tumor model that we found recapitulated the three phases of immunoediting spontaneously in immunocompetent animals. Given that a significant portion of NPK-C1 tumors reliably progressed to the escape phase, we were able to delineate cell types and mechanisms differentially prevalent in equilibrium versus escape phases. Using high-dimensional flow cytometry, we found that activated CD4+ effector T cells were enriched in regressing tumors, highlighting a role for CD4+ T cells in antitumor immunity. CD8+ T cells were also important for NPK-C1 control, specifically, central memory-like cytotoxic CD8+ T cells. Regulatory T cells (Treg), as a whole, were counterintuitively enriched in regressing tumors; however, high-dimensional analysis revealed their significant phenotypic diversity, with a number of Treg subpopulations enriched in progressing tumors. In the myeloid compartment, we found that iNOS+ dendritic cell (DC)-like cells are enriched in regressing tumors, whereas CD103+ DCs were associated with late-stage tumor progression. In total, these analyses of the NPK-C1 model provide novel insights into the roles of lymphoid and myeloid populations throughout the cancer immunoediting process and highlight a role for multidimensional, flow-based analyses to more deeply understand immune cell dynamics in the tumor microenvironment.
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Antígenos CD/inmunología , Linfocitos T CD8-positivos/inmunología , Cadenas alfa de Integrinas/inmunología , Neoplasias de la Próstata/inmunología , Escape del Tumor , Microambiente Tumoral/inmunología , Animales , Modelos Animales de Enfermedad , Citometría de Flujo , Masculino , Ratones , Ratones Endogámicos C57BL , Fenotipo , Neoplasias de la Próstata/patología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Carga Tumoral/inmunologíaRESUMEN
Plasmacytoid dendritic cells (pDCs) specialize in the production of type I IFN (IFN-I). pDCs can be depleted in vivo by injecting diphtheria toxin (DT) in a mouse in which pDCs express a diphtheria toxin receptor (DTR) transgene driven by the human CLEC4C promoter. This promoter is enriched for binding sites for TCF4, a transcription factor that promotes pDC differentiation and expression of pDC markers, including CLEC4C. Here, we found that injection of DT in CLEC4C-DTR+ mice markedly augmented Th2-dependent skin inflammation in a model of contact hypersensitivity (CHS) induced by the hapten fluorescein isothiocyanate. Unexpectedly, this biased Th2 response was independent of reduced IFN-I accompanying pDC depletion. In fact, DT treatment altered the representation of conventional dendritic cells (cDCs) in the skin-draining lymph nodes during the sensitization phase of CHS; there were fewer Th1-priming CD326+ CD103+ cDC1 and more Th2-priming CD11b+ cDC2. Single-cell RNA-sequencing of CLEC4C-DTR+ cDCs revealed that CD326+ DCs, like pDCs, expressed DTR and were depleted together with pDCs by DT treatment. Since CD326+ DCs did not express Tcf4, DTR expression might be driven by yet-undefined transcription factors activating the CLEC4C promoter. These results demonstrate that altered DC representation in the skin-draining lymph nodes during sensitization to allergens can cause Th2-driven CHS.
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Células Dendríticas/inmunología , Dermatitis por Contacto/inmunología , Interferón Tipo I/genética , Lectinas Tipo C/genética , Receptores Inmunológicos/genética , Piel/inmunología , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Dermatitis por Contacto/genética , Dermatitis por Contacto/patología , Toxina Diftérica/genética , Factor de Crecimiento Similar a EGF de Unión a Heparina/genética , Factor de Crecimiento Similar a EGF de Unión a Heparina/inmunología , Humanos , Cadenas alfa de Integrinas/genética , Cadenas alfa de Integrinas/inmunología , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas/genética , Células Th2/inmunología , Factor de Transcripción 4/genética , Factor de Transcripción 4/inmunologíaAsunto(s)
Dermatitis/inmunología , Dermatitis/patología , Urticaria/inmunología , Urticaria/patología , Antígenos CD/inmunología , Biopsia/métodos , Antígenos CD8/inmunología , Estudios Transversales , Dermatitis/diagnóstico , Eccema/diagnóstico , Eccema/inmunología , Eccema/patología , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunofenotipificación , Cadenas alfa de Integrinas/inmunología , Estudios Retrospectivos , Linfocitos T Reguladores/inmunología , Urticaria/diagnósticoRESUMEN
Tissue-resident memory CD8+ T cells (TRM ) localize to barrier tissues and mediate local protection against reinvading pathogens. Circulating central memory (TCM ) and effector memory CD8+ T cells (TEM ) also contribute to tissue recall responses, but their potential to form mucosal TRM remains unclear. Here, we employed adoptive transfer and lymphocytic choriomeningitis virus reinfection models to specifically assess secondary responses of TCM and TEM at mucosal sites. Donor TCM and TEM exhibited robust systemic recall responses, but only limited accumulation in the small intestine, consistent with reduced expression of tissue-homing and -retention molecules. Murine and human circulating memory T cells also exhibited limited CD103 upregulation following TGF-ß stimulation. Upon pathogen clearance, TCM and TEM readily gave rise to secondary TEM . TCM also formed secondary central memory in lymphoid tissues and TRM in internal tissues, for example, the liver. Both TCM and TEM failed to substantially contribute to resident mucosal memory in the small intestine, while activated intestinal TRM , but not liver TRM , efficiently reformed CD103+ TRM . Our findings demonstrate that circulating TCM and TEM are limited in generating mucosal TRM upon reinfection. This may pose important implications on cell therapy and vaccination strategies employing memory CD8+ T cells for protection at mucosal sites.
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Antígenos CD/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunidad Mucosa , Memoria Inmunológica , Cadenas alfa de Integrinas/inmunología , Inmunidad Adaptativa , Traslado Adoptivo , Animales , Antígenos CD/metabolismo , Linfocitos T CD8-positivos/clasificación , Linfocitos T CD8-positivos/citología , Diferenciación Celular/inmunología , Femenino , Humanos , Cadenas alfa de Integrinas/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Intestino Delgado/citología , Intestino Delgado/inmunología , Activación de Linfocitos , Virus de la Coriomeningitis Linfocítica/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Membrana Mucosa/citología , Membrana Mucosa/inmunología , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
Abnormal crosstalk between gut immune and the liver was involved in nonalcoholic steatohepatitis (NASH). Mice with methionine choline-deficient (MCD) diet-induced NASH presented an imbalance of pro-(IL-6 and IFN-γ) and anti-inflammatory cytokines (IL-10) in the intestine. We also clarified that the ratio of CD4+ T cells and found that the NASH mesenteric lymph node (MLN) presents decreased numbers of CD4+Th17 cells but increased numbers of CD4+CD8+FoxP3+ regulatory T cells (Tregs). Furthermore, the intestinal immune imbalance in NASH was attributed to impaired gut chemokine receptor 9 (CCR9)/chemokine ligand 25 (CCL25) signalling, which is a crucial pathway for immune cell homing in the gut. We also demonstrated that CD4+CCR9+ T cell homing was dependent on CCL25 and that the numbers and migration abilities of CD4+CCR9+ T cells were reduced in NASH. Interestingly, the analysis of dendritic cell (DC) subsets showed that the numbers and retinal dehydrogenase (RALDH) activity of CD103+CD11b+ DCs were decreased and that the ability of these cells to upregulate CD4+ T cell CCR9 expression was damaged in NASH. Taken together, impaired intestinal CCR9/CCL25 signalling induced by CD103+CD11b+ DC dysfunction contributes to the gut immune imbalance observed in NASH.
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Quimiocinas CC/metabolismo , Células Dendríticas/inmunología , Intestinos/inmunología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Receptores CCR/metabolismo , Alanina Transaminasa/sangre , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Aspartato Aminotransferasas/sangre , Antígeno CD11b/inmunología , Antígeno CD11b/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Quimiocinas CC/genética , Deficiencia de Colina/complicaciones , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Cadenas alfa de Integrinas/inmunología , Cadenas alfa de Integrinas/metabolismo , Intestinos/fisiopatología , Masculino , Metionina/deficiencia , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores CCR/genética , Transducción de SeñalRESUMEN
OBJECTIVES/HYPOTHESIS: Characterization of the localized adaptive immune response in the airway scar of patients with idiopathic subglottic stenosis (iSGS). STUDY DESIGN: Basic Science. METHODS: Utilizing 36 patients with subglottic stenosis (25 idiopathic subglottic stenosis [iSGS], 10 iatrogenic post-intubation stenosis [iLTS], and one granulomatosis with polyangiitis [GPA]) we applied immunohistochemical and immunologic techniques coupled with RNA sequencing. RESULTS: iSGS, iLTS, and GPA demonstrate a significant immune infiltrate in the subglottic scar consisting of adaptive cell subsets (T cells along with dendritic cells). Interrogation of T cell subtypes showed significantly more CD69+ CD103+ CD8+ tissue resident memory T cells (TRM ) in the iSGS airway scar than iLTS specimens (iSGS vs. iLTS; 50% vs. 28%, P = .0065). Additionally, subglottic CD8+ clones possessed T-cell receptor (TCR) sequences with known antigen specificity for viral and intracellular pathogens. CONCLUSIONS: The human subglottis is significantly enriched for CD8+ tissue resident memory T cells in iSGS, which possess TCR sequences proven to recognize viral and intracellular pathogens. These results inform our understanding of iSGS, provide a direction for future discovery, and demonstrate immunologic function in the human proximal airway. Laryngoscope, 131:610-617, 2021.