RESUMO
The kynurenine pathway (KP) is a key regulator of many important physiological processes and plays a harmful role in cancer, many neurologic conditions, and chronic viral infections. In HIV infection, KP activity is consistently associated with reduced CD4 T cell counts and elevated levels of T cell activation and viral load; it also independently predicts mortality and morbidity from non-AIDS events. Kynurenine 3-monooxygenase (KMO) is a therapeutically important target in the KP. Using the nonhuman primate model of SIV infection in rhesus macaques, we investigated whether KMO inhibition could slow the course of disease progression. We used a KMO inhibitor, CHDI-340246, to perturb the KP during early acute infection and followed the animals for 1 y to assess clinical outcomes and immune phenotype and function during pre-combination antiretroviral therapy acute infection and combination antiretroviral therapy-treated chronic infection. Inhibition of KMO in acute SIV infection disrupted the KP and prevented SIV-induced increases in downstream metabolites, improving clinical outcome as measured by both increased CD4+ T cell counts and body weight. KMO inhibition increased naive T cell frequency and lowered PD-1 expression in naive and memory T cell subsets. Importantly, early PD-1 expression during acute SIV infection predicted clinical outcomes of body weight and CD4+ T cell counts. Our data indicate that KMO inhibition in early acute SIV infection provides clinical benefit and suggest a rationale for testing KMO inhibition as an adjunctive treatment in SIV/HIV infection to slow the progression of the disease and improve immune reconstitution.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Quinurenina 3-Mono-Oxigenase/antagonistas & inibidores , Receptor de Morte Celular Programada 1/biossíntese , Pirimidinas/farmacologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Animais , Antirretrovirais/farmacologia , Peso Corporal/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Macaca mulatta , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismoRESUMO
OBJECTIVE: CD4+FoxP3+ Treg cells suppress effector T cells and prevent autoimmune disease. Treg cell function is deficient in active rheumatoid arthritis (RA), a loss which may play a role in the pathogenesis of this disease. We previously showed that a single-nucleotide polymorphism in the FCRL3 gene led to higher expression of Fc receptor-like 3 (FcRL3) on Treg cells and that FcRL3+ Treg cells are functionally deficient in comparison to FcRL3- Treg cells. This study was undertaken to investigate the potential role of FcRL3 in RA. METHODS: A cross-sectional study was performed to evaluate the FCRL3 -169 genotype and FcRL3 expression on T cell subsets, including Treg cells, in peripheral blood samples from 51 patients with RA enrolled in the University of California, San Francisco (UCSF) RA Cohort. Clinical data were obtained from the UCSF RA Cohort database. RESULTS: Patients with the FCRL3 -169C allele (genotype C/C or C/T) expressed higher levels of FcRL3 on Treg cells, and on CD8+ and γ/δ T cells, in comparison to RA patients with the T/T genotype. Higher FcRL3 expression on these T cell subpopulations correlated with RA disease activity in patients harboring the FCRL3 -169C allele. Furthermore, FcRL3 expression on Treg cells was higher in patients with erosive RA, and the FCRL3 -169C allele was overrepresented in patients with erosive RA. CONCLUSION: Our findings indicate that FcRL3 expression, which is strongly associated with the presence of the FCRL3 -169C allele, may serve as a biomarker for RA disease activity.
Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/metabolismo , Adulto , Alelos , Artrite Reumatoide/patologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Biomarcadores/metabolismo , Antígenos CD8/metabolismo , Contagem de Células , Estudos Transversais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/patologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologiaRESUMO
CD4(+)FoxP3(+) regulatory T cells (T(reg)) play a critical role in maintaining self-tolerance and inhibiting autoimmune disease. Despite being a major focus of modern immunological investigation, many aspects of T(reg) biology remain unknown. In a screen for novel candidate genes involved in human T(reg) function, we detected the expression of an autoimmune susceptibility gene, FcRL3, in T(reg) but not in conventional CD4(+) T cells. FcRL3 is an orphan receptor of unknown function with structural homology to classical Fc receptors. Numerous genetic studies have demonstrated a link between a single nucleotide polymorphism in the FCRL3 promoter and both overexpression of FcRL3 and autoimmune diseases such as rheumatoid arthritis. Given the critical role of T(reg) in suppressing autoimmunity, we sought to ascertain how expression of FcRL3 relates to the phenotype, differentiation, and function of T(reg). We show in this study that FcRL3 is expressed on a population of thymically derived T(reg) that exhibits a memory phenotype and high levels of programmed cell death-1. Purified FcRL3(+) T(reg) are less responsive to antigenic stimulation in the presence of IL-2 than their FcRL3(-) counterparts, despite intact proximal and distal IL-2 signaling as determined by phosphorylation of Stat-5 and upregulation of Bcl2. In vitro suppression assays demonstrated that FcRL3(+) T(reg) have reduced capacity to suppress the proliferation of effector T cells. These data suggest that FcRL3 expression is associated with T(reg) dysfunction that may, in turn, contribute to the loss of self-tolerance and the development of autoimmunity.
Assuntos
Antígenos CD/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Receptores Imunológicos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Antígenos CD/biossíntese , Proteínas Reguladoras de Apoptose/biossíntese , Diferenciação Celular/imunologia , Separação Celular , Citometria de Fluxo , Humanos , Ativação Linfocitária/imunologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptor de Morte Celular Programada 1 , Receptores Imunológicos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tolerância a Antígenos Próprios/imunologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismoRESUMO
Type I IFNs (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of HIV infection treated with antiretroviral therapy (ART) also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8+ T cell exhaustion. To determine whether inhibition of IFN-α might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti-IFN-α antibody followed by an analytical treatment interruption (ATI). IFN-α blockade was well-tolerated and associated with lower expression of TI-IFN-inducible genes (including those that are antiviral) and reduced tissue viral DNA (vDNA). The reduction in vDNA was further accompanied by higher innate proinflammatory plasma cytokines, expression of monocyte activation genes, IL-12-induced effector CD8+ T cell genes, increased heme/metabolic activity, and lower plasma TGF-ß levels. Upon ATI, SIV-infected, ART-suppressed nonhuman primates treated with anti-IFN-α displayed lower levels of weight loss and improved erythroid function relative to untreated controls. Overall, these data demonstrated that IFN-α blockade during ART-treated SIV infection was safe and associated with the induction of immune/erythroid pathways that reduced viral persistence during ART while mitigating the weight loss and anemia that typically ensue after ART interruption.
Assuntos
Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , DNA Viral , Infecções por HIV/tratamento farmacológico , Imunidade , Interferon-alfa , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Redução de PesoRESUMO
Gut microbes can profoundly modulate mucosal barrier-promoting Th17 cells in mammals. A salient feature of HIV/simian immunodeficiency virus (SIV) immunopathogenesis is the loss of Th17 cells, which has been linked to increased activity of the immunomodulatory enzyme, indoleamine 2,3-dioxygenase 1 (IDO 1). The role of gut microbes in this system remains unknown, and the SIV-infected rhesus macaque provides a well-described model for HIV-associated Th17 loss and mucosal immune disruption. We observed a specific depletion of gut-resident Lactobacillus during acute and chronic SIV infection of rhesus macaques, which was also seen in early HIV-infected humans. This depletion in rhesus macaques correlated with increased IDO1 activity and Th17 loss. Macaques supplemented with a Lactobacillus-containing probiotic exhibited decreased IDO1 activity during chronic SIV infection. We propose that Lactobacillus species inhibit mammalian IDO1 and thus may help to preserve Th17 cells during pathogenic SIV infection, providing support for Lactobacillus species as modulators of mucosal immune homeostasis.
Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Lactobacillus/imunologia , Macaca mulatta/imunologia , Vírus da Imunodeficiência Símia/imunologia , Células Th17/imunologia , Animais , Feminino , Infecções por HIV/imunologia , Infecções por HIV/microbiologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/microbiologia , Células Th17/microbiologiaRESUMO
HIV-mediated immune dysfunction may influence CD4(+) T cell recovery during suppressive antiretroviral therapy (ART). We analyzed cellular biomarkers of immunological inflammation, maturation, and senescence in HIV-infected subjects on early suppressive ART. We performed longitudinal analyses of peripheral immunological biomarkers of subjects on suppressive ART (n = 24) from early treatment (median 6.4 months, interquartile range [IQR] 4.8-13.9 months) to 1-2 years of follow-up (median 19.8 months, IQR 18.3-24.6 months). We performed multivariate regression to determine which biomarkers were associated with and/or predictive of CD4(+) T cell recovery. After adjusting for the pre-ART CD4(+) T cell count, age, proximal CD4(+) T cell count, and length of ART medication, the percentage of CD27(+)CD8(+) T cells remained significantly associated with the CD4(+) T cell recovery rate (ß = 0.092 cells/ul/month, P = 0.028). In HIV-infected subjects starting suppressive ART, patients with the highest percentage of CD8(+) T cells expressing CD27 had the greatest rate of CD4(+) T cell recovery.