RESUMEN
Overcoming exhaustion-associated dysfunctions and generating antigen-specific CD8 T cells with the ability to persist in the host and mediate effective long-term anti-tumor immunity is the final aim of cancer immunotherapy. To achieve this goal, immuno-modulatory properties of the common gamma-chain (γc) family of cytokines, that includes IL-2, IL-7, IL-15 and IL-21, have been used to fine-tune and/or complement current immunotherapeutic protocols. These agents potentiate CD8 T cell expansion and functions particularly in the context of immune checkpoint (IC) blockade, shape their differentiation, improve their persistence in vivo and alternatively, influence distinct aspects of the T cell exhaustion program. Despite these properties, the intrinsic impact of cytokines on CD8 T cell exhaustion has remained largely unexplored impeding optimal therapeutic use of these agents. In this review, we will discuss current knowledge regarding the influence of relevant γc cytokines on CD8 T cell differentiation and function based on clinical data and preclinical studies in murine models of cancer and chronic viral infection. We will restate the place of these agents in current immunotherapeutic regimens such as IC checkpoint blockade and adoptive cell therapy. Finally, we will discuss how γc cytokine signaling pathways regulate T cell immunity during cancer and whether targeting these pathways may sustain an effective and durable T cell response in patients.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Neoplasias/inmunología , Animales , Humanos , Inmunoterapia , Neoplasias/terapia , Transducción de SeñalRESUMEN
CD4+Foxp3+ regulatory T (TREG) cells are critical mediators of peripheral tolerance and modulators of immune responses. Functional adaptation of TREG cells, through acquisition of secondary transcription factors is critical for their effector differentiation towards local inflammatory stimuli including infections. The drivers and consequences of this adaptation of TREG cell function remain largely unknown. Using an unbiased screen, we identified receptors of the IL-1 family controlling the adaptation of TREG cells. Through respiratory infection models, we show that the IL-33 receptor (ST2) and the IL-1 receptor (IL1R1) selectively identify stable and unstable TREG cells at mucosal surfaces, respectively. IL-33, not IL-1, is specifically required for maintaining the suppressive function of TREG cells. In the absence of ST2, TREG cells are prone to lose Foxp3 expression and acquire RORγT and IL1R1, while, in the absence of IL-1R1, they maintain Foxp3 expression and resist the acquisition of a Th17 phenotype. Finally, lack of IL-1 signalling enhances the accumulation of ST2+ TREG over pro-inflammatory TREG cells in a Cryptococcus neoformans infection. These observations show that IL-1 and IL-33 exert opposing functions in controlling the functional adaptation of TREG cells, ultimately dictating the dynamics of adaptive immunity to pathogens.
Asunto(s)
Criptococosis/inmunología , Cryptococcus neoformans/fisiología , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Mucosa Respiratoria/inmunología , Linfocitos T Reguladores/fisiología , Animales , Diferenciación Celular , Células Cultivadas , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Tolerancia Inmunológica , Interleucina-1/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Tipo I de Interleucina-1/genéticaRESUMEN
Cryptococcus neoformans is a ubiquitous environmental yeast and a leading cause of invasive fungal infection in humans. The most recent estimate of global disease burden includes over 200,000 cases of cryptococcal meningitis each year. Cryptococcus neoformans expresses several virulence factors that may have originally evolved to protect against environmental threats, and human infection may be an unintended consequence of these acquired defenses. Traditionally, C. neoformans has been viewed as a purely opportunistic pathogen that targets severely immune compromised hosts; however, during the past decade the spectrum of susceptible individuals has grown considerably. In addition, the closely related strain Cryptococcus gattii has recently emerged in North America and preferentially targets individuals with intact immunity. In parallel to the changing epidemiology of cryptococcosis, an increasing role for host immunity in the pathogenesis of severe disease has been elucidated. Initially, the HIV/AIDS epidemic revealed the capacity of C. neoformans to cause host damage in the absence of adaptive immunity. Subsequently, the development and clinical implementation of highly active antiretroviral treatment (HAART) led to recognition of an immune reconstitution inflammatory syndrome (IRIS) in a subset of HIV+ individuals, demonstrating the pathological role of host immunity in disease. A post-infectious inflammatory syndrome (PIIRS) characterized by abnormal T cell-macrophage activation has also been documented in HIV-negative individuals following antifungal therapy. These novel clinical conditions illustrate the highly complex host-pathogen relationship that underlies severe cryptococcal disease and the intricate balance between tolerance and resistance that is necessary for effective resolution. In this article, we will review current knowledge of the interactions between cryptococci and mammalian hosts that result in a tolerant phenotype. Future investigations in this area have potential for translation into improved therapies for affected individuals.
Asunto(s)
Cryptococcus neoformans/inmunología , Cryptococcus neoformans/patogenicidad , Resistencia a la Enfermedad/inmunología , Tolerancia Inmunológica/inmunología , Meningitis Criptocócica/microbiología , Adaptación Fisiológica , Animales , Linfocitos T CD4-Positivos/inmunología , Cryptococcus gattii/inmunología , Células Dendríticas/inmunología , Interacciones Huésped-Patógeno , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/microbiología , Interleucina-10/metabolismo , Ratones , Factores de Virulencia/metabolismoRESUMEN
Interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1ß) are pro-inflammatory cytokines that are induced after Cryptococcus neoformans infection and activate the interleukin-1 receptor type I (IL-1RI). To establish the role of IL-1RI signaling in protection against cryptococcal infection, we analyzed wild-type (WT) and IL-1RI-deficient (IL-1RI-/-) mice on the BALB/c background. IL-1RI-/- mice had significantly reduced survival compared to WT mice after intratracheal challenge with C. neoformans 52D. Microbiological analysis showed a significant increase in the lung and brain fungal burden of IL-1RI-/- compared to WT mice beginning at weeks 1 and 4 postinfection, respectively. Histopathology showed that IL-1RI-/- mice exhibit greater airway epithelial mucus secretion and prominent eosinophilic crystals that were absent in WT mice. Susceptibility of IL-1RI-/- mice was associated with significant induction of a Th2-biased immune response characterized by pulmonary eosinophilia, M2 macrophage polarization, and recruitment of CD4+ IL-13+ T cells. Expression of pro-inflammatory [IL-1α, IL-1ß, TNFα, and monocyte chemoattractant protein 1 (MCP-1)], Th1-associated (IFNγ), and Th17-associated (IL-17A) cytokines was significantly reduced in IL-1RI-/- lungs compared to WT. WT mice also had higher expression of KC/CXCL1 and sustained neutrophil recruitment to the lung; however, antibody-mediated depletion of these cells showed that they were dispensable for lung fungal clearance. In conclusion, our data indicate that IL-1RI signaling is required to activate a complex series of innate and adaptive immune responses that collectively enhance host defense and survival after C. neoformans 52D infection in BALB/c mice.
RESUMEN
The genetic basis of natural susceptibility to progressive Cryptococcus neoformans infection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated with C. neoformans susceptibility (Cnes1, Cnes2, and Cnes3). To validate and characterize the role of Cnes2 during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2 mice 35 days after C. neoformans infection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-γ) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b(+) dendritic cells, and CD4(+) cells in B6.CBA-Cnes2 than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2 mice. Taken together, these findings demonstrate that the Cnes2 interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization following C. neoformans infection.
Asunto(s)
Cromosomas de los Mamíferos/inmunología , Criptococosis/genética , Cryptococcus neoformans/inmunología , Sitios Genéticos/inmunología , Predisposición Genética a la Enfermedad , Inmunidad Innata , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/patología , Cromosomas de los Mamíferos/química , Cruzamientos Genéticos , Criptococosis/inmunología , Criptococosis/microbiología , Criptococosis/patología , Células Dendríticas/inmunología , Células Dendríticas/microbiología , Células Dendríticas/patología , Expresión Génica , Interacciones Huésped-Patógeno , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-12/genética , Interleucina-12/inmunología , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-5/genética , Interleucina-5/inmunología , Macrófagos/inmunología , Macrófagos/microbiología , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Neutrófilos/inmunología , Neutrófilos/microbiología , Neutrófilos/patología , Fenotipo , Balance Th1 - Th2RESUMEN
Susceptibility to progressive infection with the fungus Cryptococcus neoformans is associated with an allergic pattern of lung inflammation, yet the factors that govern this host response are not clearly understood. Using a clinically relevant mouse model of inhalational infection with virulent C. neoformans H99, we demonstrate a role for IL-33-dependent signaling in host immune defense. Infection of BALB/c mice with 10(4) CFU of C. neoformans H99 caused a time-dependent induction of IL-33 with accumulation of type 2 pulmonary innate lymphoid cells and alternatively activated macrophages in the lungs as well as Th2-polarized CD4(+) T cells in draining lymph nodes. IL-33R subunit T1/ST2-deficient (T1/ST2(-/-)) mice infected with C. neoformans H99 had improved survival with a decreased fungal burden in the lungs, spleen, and brain, compared with wild-type mice. Signaling through T1/ST2 was required for the accumulation and early production of IL-5 and IL-13 by lung type 2 pulmonary innate lymphoid cells. Further analysis of T1/ST2(-/-) mice revealed increased fungicidal exudate macrophages in the lungs and decreased C. neoformans-specific Th2 cells in the mediastinal lymph nodes. T1/ST2 deficiency also diminished goblet cell hyperplasia, mucus hypersecretion, bronchoalveolar lavage eosinophilia, alternative activation of macrophages, and serum IgE. These observations demonstrate that IL-33-dependent signaling contributes to the expansion of innate type 2 immunity and subsequent Th2-biased lung immunopathology that facilitates C. neoformans growth and dissemination.
Asunto(s)
Inmunidad Adaptativa/inmunología , Criptococosis/inmunología , Inmunidad Innata/inmunología , Interleucinas/inmunología , Transducción de Señal/inmunología , Animales , Separación Celular , Criptococosis/metabolismo , Cryptococcus neoformans , Modelos Animales de Enfermedad , Citometría de Flujo , Interleucina-33 , Interleucinas/metabolismo , Enfermedades Pulmonares Fúngicas/inmunología , Ratones , Ratones Endogámicos BALB C , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Acute lung injury during bacterial infection is associated with neutrophilic inflammation, epithelial cell apoptosis, and disruption of the alveolar-capillary barrier. TLR4 is required for lung injury in animals exposed to bacterial LPS and initiates proinflammatory responses in part via the transcription factor NF-κB. Ligation of TLR4 also initiates a proapoptotic response by activating IFN-ß and STAT1-dependent genes. We recently demonstrated that mammalian target of rapamycin (mTOR), a key controller of cell growth and survival, can physically interact with STAT1 and suppress the induction of STAT1-dependent apoptosis genes. We therefore hypothesized that the mTOR inhibitor rapamycin would increase LPS-induced apoptosis and lung injury in vivo. Rapamycin increased lung injury and cellular apoptosis in C57BL/6J mice exposed to intratracheal LPS for 24 h. Rapamycin also augmented STAT1 activation, and the induction of STAT1-dependent genes that mediate cellular apoptosis (i.e., Fas, caspase-3). LPS-induced lung injury was attenuated in STAT1 knockout mice. In addition, LPS and IFN-ß-induced apoptosis was absent in cultured cells lacking STAT1, and, unlike in wild-type cells, a permissive effect of rapamycin was not observed. In contrast to its effect on STAT1, rapamycin inhibited NF-κB activation in vivo and reduced selected markers of inflammation (i.e., neutrophils in the bronchoalveolar lavage fluid, TNF-α). Therefore, although it inhibits NF-κB and neutrophilic inflammation, rapamycin augments LPS-induced lung injury and apoptosis in a mechanism that involves STAT1 and the induction of STAT1-dependent apoptosis genes.
Asunto(s)
Lesión Pulmonar Aguda/inmunología , Apoptosis/efectos de los fármacos , Lipopolisacáridos/toxicidad , Serina-Treonina Quinasas TOR/inmunología , Receptor Toll-Like 4/inmunología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/genética , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Antibacterianos/farmacología , Apoptosis/genética , Apoptosis/inmunología , Lavado Broncoalveolar , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Interferón beta/genética , Interferón beta/inmunología , Interferón beta/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , FN-kappa B/genética , FN-kappa B/inmunología , FN-kappa B/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT1/metabolismo , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
A bacterial strain was isolated and cultured from the oil excavation areas in tropical zone in southern Iran. It was affiliated with Pseudomonas. The biochemical characteristics and partial sequenced 16S rRNA gene of isolate, MR01, was identical to those of cultured representatives of the species Pseudomonas aeruginosa. This bacterium was able to produce a type of biosurfactant with excessive foam-forming properties. Compositional analysis revealed that the extracted biosurfactant was composed of high percentages lipid ( approximately 65%, w/w) and carbohydrate ( approximately 30%, w/w) in addition to a minor fraction of protein ( approximately 4%, w/w). The best production of 2.1g/l was obtained when the cells were grown on minimal salt medium containing 1.2% (w/v) glucose and 0.1% (w/v) ammonium sulfate supplemented with 0.1% (w/v) isoleucine at 37 degrees C and 180rpm after 2 days. The optimum biosurfactant production pH value was found to be 8.0. The MR01 could reduce surface tension to 28mN/m and emulsified hexadecane up to E24 approximately 70. The results obtained from time course study indicated that the surface tension reduction and emulsification potential was increased in the same way to cell growth. However, maximum biosurfactant production occurred and established in the stationary growth phase (after 84h). Fourier Transform Infrared spectrum of extracted biosurfactant indicates the presence of carboxyl, amine, hydroxyl and methoxyl functional groups. Thermogram of biosurfactant demonstrated three sharp endothermic peaks placing between 200 and 280 degrees C. The core holder flooding experiments demonstrated that the oil recovery efficiencies varied from 23.7% to 27.1% of residual oil.