RESUMEN
Infectious, inflammatory and autoimmune conditions present differently in males and females. SARS-CoV-2 infection in naive males is associated with increased risk of death, whereas females are at increased risk of long COVID1, similar to observations in other infections2. Females respond more strongly to vaccines, and adverse reactions are more frequent3, like most autoimmune diseases4. Immunological sex differences stem from genetic, hormonal and behavioural factors5 but their relative importance is only partially understood6-8. In individuals assigned female sex at birth and undergoing gender-affirming testosterone therapy (trans men), hormone concentrations change markedly but the immunological consequences are poorly understood. Here we performed longitudinal systems-level analyses in 23 trans men and found that testosterone modulates a cross-regulated axis between type-I interferon and tumour necrosis factor. This is mediated by functional attenuation of type-I interferon responses in both plasmacytoid dendritic cells and monocytes. Conversely, testosterone potentiates monocyte responses leading to increased tumour necrosis factor, interleukin-6 and interleukin-15 production and downstream activation of nuclear factor kappa B-regulated genes and potentiation of interferon-γ responses, primarily in natural killer cells. These findings in trans men are corroborated by sex-divergent responses in public datasets and illustrate the dynamic regulation of human immunity by sex hormones, with implications for the health of individuals undergoing hormone therapy and our understanding of sex-divergent immune responses in cisgender individuals.
Asunto(s)
Testosterona , Personas Transgénero , Adulto , Femenino , Humanos , Masculino , Conjuntos de Datos como Asunto , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/metabolismo , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-15/inmunología , Interleucina-15/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Monocitos/inmunología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , FN-kappa B/metabolismo , Caracteres Sexuales , Testosterona/efectos adversos , Testosterona/inmunología , Testosterona/farmacología , Testosterona/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The cytokine IFNγ is a principal effector of macrophage activation and immune resistance to mycobacterial infection; however, pathogenic mycobacteria are capable of surviving in IFNγ-activated macrophages by largely unknown mechanisms. In this study, we find that pathogenic mycobacteria, including M. bovis BCG and M. tuberculosis can sense IFNγ to promote their proliferative activity and virulence phenotype. Moreover, interaction with the host intracellular environment increases the susceptibility of mycobacteria to IFNγ through upregulating expression of mmpL10, a mycobacterial IFNγ receptor, thereby facilitating IFNγ-dependent survival and growth of mycobacteria in macrophages. Transmission electron microscopy analysis reveals that IFNγ triggers the secretion of extracellular vesicles, an essential virulence strategy of intracellular mycobacteria, while proteomics identifies numerous pivotal IFNγ-induced effectors required for mycobacterial infection in macrophages. Our study suggests that sensing host IFNγ is a crucial virulence mechanism used by pathogenic mycobacteria to survive and proliferate inside macrophages.
Asunto(s)
Interferón gamma , Macrófagos , Ratones Endogámicos C57BL , Mycobacterium tuberculosis , Interferón gamma/metabolismo , Interferón gamma/inmunología , Macrófagos/microbiología , Macrófagos/metabolismo , Macrófagos/inmunología , Animales , Ratones , Mycobacterium tuberculosis/patogenicidad , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/metabolismo , Mycobacterium bovis/inmunología , Mycobacterium bovis/metabolismo , Humanos , Interacciones Huésped-Patógeno/inmunología , Virulencia , Receptores de Interferón/metabolismo , Receptores de Interferón/genética , Receptor de Interferón gamma , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/inmunología , Activación de Macrófagos , Infecciones por Mycobacterium/microbiología , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/metabolismo , Infecciones por Mycobacterium/patologíaRESUMEN
Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a driver for immunotherapy resistance in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFNγ)-STAT1 signaling pathway, and higher PRMT3 expression levels correlate with reduced numbers of tumor-infiltrating CD8+ T cells and poorer response to ICB. Genetic depletion or pharmacological inhibition of PRMT3 elicits an influx of T cells into tumors and reduces tumor size in HCC mouse models. Mechanistically, PRMT3 methylates HSP60 at R446 to induce HSP60 oligomerization and maintain mitochondrial homeostasis. Targeting PRMT3-dependent HSP60 methylation disrupts mitochondrial integrity and increases mitochondrial DNA (mtDNA) leakage, which results in cGAS/STING-mediated anti-tumor immunity. Lastly, blocking PRMT3 functions synergize with PD-1 blockade in HCC mouse models. Our study thus identifies PRMT3 as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.
Asunto(s)
Carcinoma Hepatocelular , Chaperonina 60 , Neoplasias Hepáticas , Proteínas de la Membrana , Nucleotidiltransferasas , Proteína-Arginina N-Metiltransferasas , Transducción de Señal , Animales , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/genética , Humanos , Ratones , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Chaperonina 60/metabolismo , Chaperonina 60/genética , Línea Celular Tumoral , Metilación , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Mitocondrias/metabolismo , Ratones Endogámicos C57BL , ADN Mitocondrial/genética , ADN Mitocondrial/inmunología , ADN Mitocondrial/metabolismo , Interferón gamma/metabolismo , Interferón gamma/inmunología , MasculinoRESUMEN
Background: To effectively control tuberculosis (TB), it is crucial to distinguish between active TB disease and latent TB infection (LTBI) to provide appropriate treatment. However, no such tests are currently available. Immune responses associated with active TB and LTBI are dynamic and exhibit distinct patterns. Comparing these differences is crucial for developing new diagnostic methods and understanding the etiology of TB. This study aimed to investigate the relationship between pro- and anti-inflammatory CD4+ cytokine production following stimulation with two types of latency-associated Mycobacterium tuberculosis (M.tb) antigens to allow differentiation between active TB and LTBI. Methods: Cryopreserved PBMCs from patients with active TB disease or LTBI were stimulated overnight with replication-related antigen [ESAT-6/CFP-10 (E/C)] or two latency-associated antigens [heparin-binding hemagglutinin (HBHA) and alpha-crystallin-like protein (Acr)]. Responses were analyzed using multiparameter flow cytometry: active TB disease (n=15), LTBI (n=15) and ELISA: active TB disease (n=26) or LTBI (n=27). Results: CD4+ central memory T cells (Tcm) specific to E/C and CD4+ effector memory T cells specific to Acr and HBHA were higher in LTBI than in TB patients. IFN-γ+Tcm and IL-17+ Tem cells was higher in the LTBI group (p= 0.012 and p=0.029 respectively), but IL-10+ Tcm was higher in the active TB group (p= 0.029) following HBHA stimulation. Additionally, following stimulation with HBHA, IL-10 production from CD4+ T cells was significantly elevated in patients with active TB compared to those with LTBI (p= 0.0038), while CD4+ T cell production of IL-17 and IFN-γ was significantly elevated in LTBI compared to active TB (p= 0.0076, p< 0.0001, respectively). HBHA also induced more CCR6+IL-17+CD4Tcells and IL-17+FoxP3+CD25+CD4Tcells in LTBI than in TB patients (P=0.026 and P=0.04, respectively). HBHA also induced higher levels of IFN-γ+IL-10+CD4+ T cells in patients with active TB (Pp=0.03) and higher levels of IFN-γ+IL-17+ CD4+ T cells in those with LTBI (p=0.04). HBHA-specific cytokine production measured using ELISA showed higher levels of IFN-γ in participants with LTBI (P=0.004) and higher levels of IL-10 in those with active TB (P=0.04). Conclusion: Stimulation with HBHA and measurement of CD4+ T cell production of IFN-γ, IL-10, and IL-17 could potentially differentiate active TB from LTBI. The characteristics of cytokine-expressing cells induced by HBHA also differed between participants with active TB and LTBI.
Asunto(s)
Antígenos Bacterianos , Linfocitos T CD4-Positivos , Interferón gamma , Interleucina-10 , Interleucina-17 , Tuberculosis Latente , Mycobacterium tuberculosis , Tuberculosis , Humanos , Masculino , Femenino , Linfocitos T CD4-Positivos/inmunología , Adulto , Interleucina-17/inmunología , Interleucina-17/metabolismo , Mycobacterium tuberculosis/inmunología , Interleucina-10/inmunología , Interferón gamma/metabolismo , Interferón gamma/inmunología , Persona de Mediana Edad , Tuberculosis Latente/inmunología , Tuberculosis/inmunología , Antígenos Bacterianos/inmunología , Anciano , Adulto Joven , LectinasRESUMEN
Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing.
Asunto(s)
Interleucina-10 , Macrófagos , Ratones Endogámicos C57BL , Linfocitos T Reguladores , Cicatrización de Heridas , Animales , Linfocitos T Reguladores/inmunología , Cicatrización de Heridas/inmunología , Interleucina-10/metabolismo , Interleucina-10/genética , Humanos , Ratones , Macrófagos/inmunología , Masculino , Monocitos/inmunología , Piel/inmunología , Interferón gamma/metabolismo , Interferón gamma/inmunología , FemeninoRESUMEN
Bacille-Calmette-Guérin (BCG) is the only approved vaccine against Mycobacterium tuberculosis (MTB), offering protection not only against tuberculosis (TB) but also non-related infections. 'Trained immunity' of innate immune cells is considered one of the mechanisms of this broad protection derived through BCG. Here, we investigated the effect of BCG on Natural Killer (NK) cells, a key innate immune cell type, and their subsequent responses to mycobacterial and HIV antigens. We found that BCG-induced KLRG1+ NK cells exhibit significantly higher production of IFNγ, compared to KLRG1- cells, indicating their memory-like responses upon exposure to these antigens (p < 0.05). These findings may be important in regions of high burden of HIV and TB where BCG is routinely administered.
Asunto(s)
Vacuna BCG , Infecciones por VIH , Memoria Inmunológica , Interferón gamma , Células Asesinas Naturales , Lectinas Tipo C , Mycobacterium tuberculosis , Receptores Inmunológicos , Tuberculosis , Células Asesinas Naturales/inmunología , Receptores Inmunológicos/inmunología , Memoria Inmunológica/inmunología , Lectinas Tipo C/inmunología , Lectinas Tipo C/metabolismo , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Vacuna BCG/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Infecciones por VIH/inmunología , Antígenos Bacterianos/inmunología , Antígenos Virales/inmunología , Inmunización/métodosRESUMEN
SjÓ§gren's syndrome (SS), also known as Sjögren's disease, is a chronic autoimmune condition predominantly affecting the salivary and lacrimal glands. The disease is driven by autoimmune responses involving the activation and actions of major innate- and adaptive immune cell subsets. However, the specific characteristics and roles of regulatory T cells (Tregs) in SS remain elusive. This study seeks to clarify the main phenotypic and functional attributes of Tregs in the salivary glands and their draining lymph nodes in murine models of SS. Our flow cytometric analysis revealed that Tregs in the salivary gland-draining lymph nodes of female non-obese diabetic (NOD) mice, a spontaneous model of SS, exhibited a greater proportion of activated Tregs and fewer resting Tregs compared to Balb/c mice. Furthermore, Tregs from the salivary gland-draining lymph nodes of female C57BL/6.NOD-Aec1Aec2 (B6.NOD-Aec) mice, a model for primary SS, demonstrated significantly lower IL-10 production but markedly higher IFNγ- and IL-17 production than their C57BL/6 counterparts. Additionally, treatment of C57BL/6 Tregs with IL-7, a cytokine critical for SS pathogenesis, resulted in diminished IL-10 production and enhanced IFNγ and IL-17 production in these cells. Notably, the alterations in B6.NOD-Aec Tregs also included an increased expression of the immune-inhibitory molecule CTLA-4 compared to the C57BL/6 Tregs. Intriguingly, in vitro co-cultures of Tregs with conventional CD4 T cells and other key immune populations from lymph nodes indicated that Tregs from salivary gland-draining lymph nodes of both B6.NOD-Aec and C57BL/6 strains exhibited comparable and limited immunosuppressive effects on the proliferation and function of conventional CD4 T cells. The ability of B6.NOD-Aec Tregs to directly inflict damages to salivary gland epithelial tissues and contribute to SS pathologies through IFNγ and IL-17 that they produce warrants further investigations. In addition, enhancing the relatively weak immunosuppressive capacities of these Tregs may also serve as a viable strategy to alleviate the SS phenotype in the mouse models and potentially in patients.
Asunto(s)
Modelos Animales de Enfermedad , Ganglios Linfáticos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Glándulas Salivales , Síndrome de Sjögren , Linfocitos T Reguladores , Animales , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/patología , Linfocitos T Reguladores/inmunología , Femenino , Ratones , Glándulas Salivales/inmunología , Glándulas Salivales/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-17/inmunología , Interleucina-10/inmunología , Interleucina-7/inmunologíaRESUMEN
BACKGROUND: Cannabidiol (CBD), the major non-psychoactive component of cannabis, exhibits anti-inflammatory properties, but less is known about the immunomodulatory potential of CBD on activated natural killer (NK) cells and/or their targets. Many tumor cells present heat shock protein 70 (Hsp70) on their cell surface in a tumor-specific manner and although a membrane Hsp70 (mHsp70) positive phenotype serves as a target for Hsp70-activated NK cells, a high mHsp70 expression is associated with tumor aggressiveness. This study investigated the immuno-modulatory potential of CBD on NK cells stimulated with TKD Hsp70 peptide and IL-2 (TKD+IL-2) and also on HCT116 p53wt and HCT116 p53-/- colorectal cancer cells exhibiting high and low basal levels of mHsp70 expression. RESULTS: Apart from an increase in the density of NTB-A and a reduced expression of LAMP-1, the expression of all other activatory NK cell receptors including NKp30, NKG2D and CD69 which are significantly up-regulated after stimulation with TKD+IL-2 remained unaffected after a co-treatment with CBD. However, the release of major pro-inflammatory cytokines by NK cells such as interferon-γ (IFN-γ) and the effector molecule granzyme B (GrzB) was significantly reduced upon CBD treatment. With respect to the tumor target cells, CBD significantly reduced the elevated expression of mHsp70 but had no effect on the low basal mHsp70 expression. Expression of other NK cell ligands such as MICA and MICB remained unaffected, and the NK cell ligands ULBP and B7-H6 were not expressed on these target cells. Consistent with the reduced mHsp70 expression, treatment of both effector and target cells with CBD reduced the killing of high mHsp70 expressing tumor cells by TKD+IL-2+CBD pre-treated NK cells but had no effect on the killing of low mHsp70 expressing tumor cells. Concomitantly, CBD treatment reduced the TKD+IL-2 induced increased release of IFN-γ, IL-4, TNF-α and GrzB, but CBD had no effect on the release of IFN-α when NK cells were co-incubated with tumor target cells. CONCLUSION: Cannabidiol (CBD) may potentially diminish the anti-tumor effectiveness of TKD+IL-2 activated natural killer (NK) cells.
Asunto(s)
Cannabidiol , Proteínas HSP70 de Choque Térmico , Células Asesinas Naturales , Activación de Linfocitos , Humanos , Cannabidiol/farmacología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Proteínas HSP70 de Choque Térmico/metabolismo , Células HCT116 , Factores Inmunológicos/farmacología , Interleucina-2/metabolismo , Interleucina-2/inmunología , Granzimas/metabolismo , Interferón gamma/metabolismo , Interferón gamma/inmunología , Línea Celular Tumoral , Citotoxicidad Inmunológica/efectos de los fármacosRESUMEN
Entamoeba histolytica, the causative agent of amebiasis, is one of the top three parasitic causes of mortality worldwide. However, no vaccine exists against amebiasis. Using a lead candidate vaccine containing the LecA fragment of Gal-lectin and GLA-3M-052 liposome adjuvant, we immunized rhesus macaques via intranasal or intramuscular routes. The vaccine elicited high-avidity functional humoral responses as seen by the inhibition of amebic attachment to mammalian target cells by plasma and stool antibodies. Importantly, antigen-specific IFN-γ-secreting peripheral blood mononuclear cells (PBMCs) and IgG/IgA memory B cells (BMEM) were detected in immunized animals. Furthermore, antigen-specific antibody and cellular responses were maintained for at least 8 months after the final immunization as observed by robust LecA-specific BMEM as well as IFN-γ+ PBMC responses. Overall, both intranasal and intramuscular immunizations elicited a durable and functional response in systemic and mucosal compartments, which supports advancing the LecA+GLA-3M-052 liposome vaccine candidate to clinical testing.
Asunto(s)
Administración Intranasal , Anticuerpos Antiprotozoarios , Entamoeba histolytica , Entamebiasis , Interferón gamma , Leucocitos Mononucleares , Liposomas , Macaca mulatta , Vacunas Antiprotozoos , Animales , Entamoeba histolytica/inmunología , Liposomas/inmunología , Liposomas/administración & dosificación , Vacunas Antiprotozoos/inmunología , Vacunas Antiprotozoos/administración & dosificación , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/inmunología , Leucocitos Mononucleares/inmunología , Entamebiasis/prevención & control , Entamebiasis/inmunología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Inyecciones Intramusculares , Inmunogenicidad Vacunal , Adyuvantes de Vacunas/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Linfocitos B/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina A/sangre , Antígenos de Protozoos/inmunología , Inmunidad Humoral , Memoria Inmunológica , Proteínas Protozoarias/inmunologíaRESUMEN
A vast body of evidence provides support to a central role of exaggerated production of interferon-γ (IFN-γ) in causing hypercytokinemia and signs and symptoms of hemophagocytic lymphohistiocytosis (HLH). In this chapter, we will describe briefly the roles of IFN-γ in innate and adaptive immunity and in host defense, summarize results from animal models of primary HLH and secondary HLH with particular emphasis on targeted therapeutic approaches, review data on biomarkers associated with activation of the IFN-γ pathway, and discuss initial efficacy and safety results of IFN-γ neutralization in humans.
Asunto(s)
Síndrome de Liberación de Citoquinas , Inmunidad Innata , Interferón gamma , Linfohistiocitosis Hemofagocítica , Humanos , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/etiología , Interferón gamma/inmunología , Animales , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Inmunidad Innata/efectos de los fármacos , Inmunidad Adaptativa/efectos de los fármacosRESUMEN
NKT cells are innate-like T cells, recruited to the skin during viral infection, yet their contributions to long-term immune memory to viruses are unclear. We identified granzyme K, a product made by cytotoxic cells including NKT cells, as linked to induction of Th1-associated antibodies during primary dengue virus (DENV) infection in humans. We examined the role of NKT cells in vivo using DENV-infected mice lacking CD1d-dependent (CD1ddep) NKT cells. In CD1d-KO mice, Th1-polarized immunity and infection resolution were impaired, which was dependent on intrinsic NKT cell production of IFN-γ, since it was restored by adoptive transfer of WT but not IFN-γ-KO NKT cells. Furthermore, NKT cell deficiency triggered immune bias, resulting in higher levels of Th2-associated IgG1 than Th1-associated IgG2a, which failed to protect against a homologous DENV rechallenge and promoted antibody-dependent enhanced disease during secondary heterologous infections. Similarly, Th2 immunity, typified by a higher IgG4/IgG3 ratio, was associated with worsened human disease severity during secondary infections. Thus, CD1ddep NKT cells establish Th1 polarity during the early innate response to DENV, which promotes infection resolution, memory formation, and long-term protection from secondary homologous and heterologous infections in mice, with consistent associations observed in humans. These observations illustrate how early innate immune responses during primary infections can influence secondary infection outcomes.
Asunto(s)
Anticuerpos Antivirales , Antígenos CD1d , Virus del Dengue , Dengue , Interferón gamma , Ratones Noqueados , Células T Asesinas Naturales , Células TH1 , Animales , Virus del Dengue/inmunología , Células TH1/inmunología , Células T Asesinas Naturales/inmunología , Ratones , Dengue/inmunología , Antígenos CD1d/inmunología , Antígenos CD1d/genética , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Humanos , Interferón gamma/inmunología , Inmunoglobulina G/inmunología , Granzimas/inmunología , Células Th2/inmunología , Memoria InmunológicaRESUMEN
The major histocompatibility complex class II (MHCII) molecules are crucial elements of the adaptive immune system, essential for orchestrating immune responses against foreign pathogens. However, excessive expression of MHCII can disrupt normal physiological functions. Therefore, the host employs various mechanisms to regulate MHCII expression and maintain immune homeostasis. Despite this importance, limited studies have explored the negative regulation of MHCII transcription in bony fish. In this study, we found that interferon h (IFNh), a subtype of type I IFN in sea perch Lateolabrax japonicus, could inhibit the activation of IFNγ induced-MHCII expression by modulating the transcription of the class II major histocompatibility complex transactivator (CIITA). Transcriptome analysis revealed 57 up-regulated and 69 down-regulated genes in cells treated with both IFNγ and IFNh compared to those treated with IFNγ alone. To maintain cellular homeostasis, interferon regulatory factor 9 (IRF9) was up-regulated following IFNγ stimulation, thereby preventing MHCII overexpression. Mechanistically, IRF9 bound to the CIITA promoter and suppressed its expression activated by IRF1. Furthermore, IRF9 inhibited the promoter activity of both MHCII-α and MHCII-ß induced by CIITA. Our findings highlight the roles of IFNh and IRF9 as suppressors regulating MHCII expression at different hierarchical levels. This study provides insights into the intricate regulation of antigen presentation and the foundation for further exploration of the interaction mechanisms between aquatic virus and fish.
Asunto(s)
Proteínas de Peces , Interferón gamma , Animales , Proteínas de Peces/genética , Proteínas de Peces/inmunología , Interferón gamma/genética , Interferón gamma/inmunología , Regulación de la Expresión Génica/inmunología , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/genética , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/inmunología , Inmunidad Innata/genética , Perfilación de la Expresión Génica/veterinaria , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Proteínas Nucleares , TransactivadoresRESUMEN
Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Guérin disease and tuberculosis3. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos , Células Madre Pluripotentes Inducidas , Factor de Necrosis Tumoral alfa , Humanos , Factor de Necrosis Tumoral alfa/metabolismo , Masculino , Adulto , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/inmunología , Células Madre Pluripotentes Inducidas/citología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/deficiencia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Femenino , Estallido Respiratorio , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/genética , Macrófagos/inmunología , Macrófagos/microbiología , Macrófagos/metabolismo , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/microbiología , Interferón gamma/inmunología , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/farmacología , Homocigoto , Receptores Tipo I de Factores de Necrosis Tumoral/deficiencia , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Mycobacterium tuberculosis/inmunologíaRESUMEN
Cancer cells frequently alter their lipids to grow and adapt to their environment1-3. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+ T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.
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Linfocitos T CD8-positivos , Glicoesfingolípidos , Receptor de Interferón gamma , Interferón gamma , Proteínas Proto-Oncogénicas p21(ras) , Transducción de Señal , Escape del Tumor , Animales , Glicoesfingolípidos/metabolismo , Glicoesfingolípidos/biosíntesis , Ratones , Humanos , Interferón gamma/metabolismo , Interferón gamma/inmunología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Femenino , Línea Celular Tumoral , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/patología , Neoplasias/metabolismo , Proliferación Celular , Receptores de Interferón/metabolismo , Receptores de Interferón/genética , Receptores de Interferón/deficiencia , Masculino , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Esfingolípidos/metabolismo , Esfingolípidos/biosíntesis , Evasión Inmune , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ratones Endogámicos C57BLRESUMEN
Anti-interferon-γ autoantibodies (AIGAs) syndrome is susceptible to disseminated opportunistic infections due to increased AIGAs, but its clinical immunological characteristics remain unrecognized. We conducted a prospective cohort study between January 2021 and December 2023, recruiting patients with opportunistic infections who were categorized into AIGAs-positive and AIGAs-negative groups. Clinical immunological data and outcomes were documented. A subset of AIGAs-positive patients received glucocorticoid treatment, and its effectiveness was evaluated. A total of 238 patients were enrolled, with 135 AIGAs-positive and 103 AIGAs-negative patients. AIGAs-positive patients showed higher rates of multiple pathogen dissemination, shorter progression-free survival (PFS), and increased exacerbation frequency. They also showed elevated erythrocyte sedimentation rate (ESR), globulin (GLB), immunoglobulin (Ig)G, IgE, and IgG4 levels. Among the 70 AIGAs-positive patients monitored for at least six months, three subtypes were identified: high AIGAs titer with immune damage, high AIGAs titer without immune damage, and low AIGAs titer without immune damage. Of the 55 patients followed for 1 year, decreasing AIGAs titer and immune indices (GLB, IgG, IgE, IgG4) were observed. Among the 31 patients with high AIGAs titer and immune damage treated with low-dose glucocorticoids at the stable phase, reductions were observed in immune indices and AIGAs titer in 67.74% of cases. In summary, AIGAs-positive patients exhibit infectious and immunological characteristics. Elevated AIGAs, IgG, IgG4, and IgE indicate abnormal immune damages. AIGAs titer generally decrease over time. Stable-phase AIGAs-positive patients can be categorized into three subtypes, with those having high AIGAs titer and increased immune indices potentially benefitting from glucocorticoid treatment.
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Autoanticuerpos , Interferón gamma , Humanos , Estudios Prospectivos , Masculino , Femenino , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Interferón gamma/sangre , Interferón gamma/inmunología , Anciano , Adulto , Glucocorticoides/uso terapéutico , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/tratamiento farmacológico , Síndrome , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunologíaRESUMEN
Natural killer (NK) cells can be effective immunotherapeutic anti-cancer agents due to their ability to selectively target and kill tumor cells. This activity is modulated by the interaction of NK cell receptors with inhibitory ligands on the surface of target cells. NK cell inhibitory ligands can be upregulated on tumor cell surfaces in response to interferon-gamma (IFN-γ), a cytokine which is produced by activated NK cells. We hypothesized that the resistance of tumor cells to NK cell killing could be overcome by expression of the parainfluenza virus 5 (PIV5) V protein, which has known roles in blocking IFN-γ signaling. This was tested with human PM21-NK cells produced through a previously developed particle-based method which yields superior NK cells for immunotherapeutic applications. Infection of human SK-N-SH neuroblastoma cells with PIV5 blocked IFN-γ-mediated upregulation of three NK cell inhibitory ligands and enhanced in vitro killing of these tumor cells by PM21-NK cells. SK-N-SH cells transduced to constitutively express the V protein alone were resistant to IFN-γ-mediated increases in cell surface expression of NK cell inhibitory ligands. Real-time in vitro cell viability assays demonstrated that V protein expression in SK-N-SH cells was sufficient to increase PM21-NK cell-mediated killing. Toward a potential therapeutic application, transient lentiviral delivery of the V gene also enhanced PM21-NK cell killing in vitro. Our results provide the foundation for novel therapeutic applications of V protein expression in combination with ex vivo NK cell therapy to effectively increase the killing of tumor cells.
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Interferón gamma , Células Asesinas Naturales , Neuroblastoma , Virus de la Parainfluenza 5 , Regulación hacia Arriba , Humanos , Células Asesinas Naturales/inmunología , Interferón gamma/metabolismo , Interferón gamma/inmunología , Neuroblastoma/inmunología , Línea Celular Tumoral , Virus de la Parainfluenza 5/inmunología , Virus de la Parainfluenza 5/genética , Ligandos , Citotoxicidad Inmunológica , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
Cervical cancer is the fourth most common cancer in females. Genome-wide association studies (GWASs) have proposed cervical cancer susceptibility variants at the HLA locus on chromosome 6p21. To corroborate these findings and investigate their functional impact in cervical tissues and cell lines, we genotyped nine variants from cervical cancer GWASs (rs17190106, rs535777, rs1056429, rs2763979, rs143954678, rs113937848, rs3117027, rs3130214, and rs9477610) in a German hospital-based series of 1122 invasive cervical cancers, 1408 dysplasias, and 1196 healthy controls. rs17190106, rs1056429 and rs143954678/rs113937848 associated with cervical malignancies overall, while rs17190106 and rs535777 associated specifically with invasive cancer (OR = 0.69, 95% CI = 0.55-0.86, p = 0.001) or adenocarcinomas (OR = 1.63, 95%CI = 1.17-2.27, p = 0.004), respectively. We tested these and one previously genotyped GWAS variant, rs9272117, for potential eQTL effects on 36 gene transcripts at the HLA locus in 280 cervical epithelial tissues. The strongest eQTL pairs were rs9272117 and HLA-DRB6 (p = 1.9x10E-5), rs1056429 and HLA-DRB5 (p = 2.5x10E-4), and rs535777 and HLA-DRB1 (p = 2.7x10E-4). We also identified transcripts that were specifically upregulated (DDX39B, HCP5, HLA-B, LTB, NFKBIL1) or downregulated (HLA-C, HLA-DPB2) in HPV+ or HPV16+ samples. In comparison, treating cervical epithelial cells with proinflammatory cytokine γ-IFN led to a dose-dependent induction of HCP5, HLA-B, HLA-C, HLA-DQB1, HLA-DRB1, HLA-DRB6, and repression of HSPA1L. Taken together, these results identify relevant genes from both the MHC class I and II regions that are inflammation-responsive in cervical epithelium and associate with HPV (HCP5, HLA-B, HLA-C) and/or with genomic cervical cancer risk variants (HLA-DRB1, HLA-DRB6). They may thus constitute important contributors to the immune escape of precancerous cells after HPV-infection.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Neoplasias del Cuello Uterino , Humanos , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/inmunología , Femenino , Genotipo , Estudios de Casos y Controles , Antígenos HLA/genética , Alelos , Persona de Mediana Edad , Adulto , Interferón gamma/genética , Interferón gamma/inmunología , Línea Celular TumoralRESUMEN
Various organ allografts differ in their propensity to be spontaneously accepted without any immunosuppressive treatment. Understanding the mechanisms behind these differences can aid in managing alloimmune responses in general. C57BL/6 mice naturally accept DBA/2J kidney allografts, forming tertiary lymphoid organs containing regulatory T cells (rTLOs), crucial for graft acceptance. In this issue of the JCI, Yokose and colleagues revealed that rTLOs promote conversion of cytotoxic alloreactive CD8+ T cells into exhausted/regulatory ones, through an IFN-γ-mediated mechanism. Their study provides insights into tolerance development that could help promote the acceptance of grafts at higher risk of rejection.
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Linfocitos T CD8-positivos , Interferón gamma , Trasplante de Riñón , Linfocitos T Reguladores , Animales , Ratones , Linfocitos T Reguladores/inmunología , Linfocitos T CD8-positivos/inmunología , Interferón gamma/inmunología , Interferón gamma/genética , Interferón gamma/metabolismo , Tolerancia al Trasplante/inmunología , Humanos , Ratones Endogámicos C57BL , Rechazo de Injerto/inmunología , Ratones Endogámicos DBA , Riñón/inmunología , Riñón/metabolismo , AloinjertosRESUMEN
Familial forms of hemophagocytic lymphohistiocytosis (HLH) are caused by loss-of-function mutations in genes encoding perforin as well as those required for release of perforin-containing cytotoxic granule constituent. Perforin is expressed by subsets of CD8+ T cells and NK cells, representing lymphocytes that share mechanism of target cell killing yet display distinct modes of target cell recognition. Here, we highlight recent findings concerning the genetics of familial HLH that implicate CD8+ T cells in the pathogenesis of HLH and discuss mechanistic insights from animal models as well as patients that reveal how CD8+ T cells may contribute to or drive disease, at least in part through release of IFN-γ. Intriguingly, CD8+ T cells and NK cells may act differentially in severe hyperinflammatory diseases such as HLH. We also discuss how CD8+ T cells may promote or drive pathology in other cytokine release syndromes (CSS). Moreover, we review the molecular mechanisms underpinning CD8+ T cell-mediated lymphocyte cytotoxicity, key to the development of familial HLH. Together, recent insights to the pathophysiology of CSS in general and HLH in particular are providing promising new therapeutic targets.
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Linfocitos T CD8-positivos , Síndrome de Liberación de Citoquinas , Linfohistiocitosis Hemofagocítica , Humanos , Linfocitos T CD8-positivos/inmunología , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/genética , Animales , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/genética , Células Asesinas Naturales/inmunología , Perforina/genética , Perforina/metabolismo , Citotoxicidad Inmunológica/genética , Interferón gamma/inmunología , Interferón gamma/genética , Interferón gamma/metabolismoRESUMEN
A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) that we refer to as 'resisters' (RSTR) show evidence of IFN-γ- T cell responses to Mtb-specific antigens despite serially negative results on clinical testing. Here we found that Mtb-specific T cells in RSTR were clonally expanded, confirming the priming of adaptive immune responses following Mtb exposure. RSTR CD4+ T cells showed enrichment of TH17 and regulatory T cell-like functional programs compared to Mtb-specific T cells from individuals with latent Mtb infection. Using public datasets, we showed that these TH17 cell-like functional programs were associated with lack of progression to active tuberculosis among South African adolescents with latent Mtb infection and with bacterial control in nonhuman primates. Our findings suggested that RSTR may successfully control Mtb following exposure and immune priming and established a set of T cell biomarkers to facilitate further study of this clinical phenotype.