RESUMO
Cytokines of the common-γ receptor chain (γc) family are crucial for T-cell differentiation and dysregulation of γc cytokine pathways is involved in the pathogenesis of autoimmune diseases. There is increasing evidence that the availability of the γc receptor (CD132) for the associated receptor chains has implications for T-cell functions. Here we studied the influence of differential γc expression on the expression of the IL-2Rα (CD25), the IL-7Rα (CD127) and the differentiation of activated naïve T cells. We fine-tuned the regulation of γc expression in human primary naïve T cells by lentiviral transduction using small hairpin (sh)RNAs and γc cDNA. Differential γc levels were then analysed for effects on T-cell phenotype and function after activation. Differential γc expression markedly affected IL-2Rα and IL-7Rα expression on activated naïve T cells. High γc expression (γc-high) induced significantly higher expression of IL-2Rα and re-expression of IL-7Rα after activation. Inhibition of γc caused lower IL-2Rα/IL-7Rα expression and impaired proliferation of activated naïve T cells. In contrast, γc-high T cells secreted significantly higher concentrations of effector cytokines (i.e., IFN-γ, IL-6) and showed higher cytokine-receptor induced STAT5 phosphorylation during initial stages as well as persistently higher pSTAT1 and pSTAT3 levels after activation. Finally, accelerated transition towards a CD45RO expressing effector/memory phenotype was seen especially for CD4+ γc-high naïve T cells. These results suggested that high expression of γc promotes expression of IL-2Rα and IL-7Rα on activated naïve T cells with significant effects on differentiation and effector cytokine expression.
Assuntos
Diferenciação Celular , Ativação Linfocitária , Humanos , Diferenciação Celular/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Receptores de Interleucina-7/metabolismo , Receptores de Interleucina-7/genética , Células Cultivadas , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transdução de Sinais , Fosforilação , Fator de Transcrição STAT5/metabolismo , Regulação da Expressão GênicaRESUMO
Host immune response is key for protection in tuberculosis, but the causative agent, Mycobacterium (M.) tuberculosis, manages to survive despite immune surveillance. Key mechanisms of immune protection have been identified, but the role of immunopathology in the peripheral blood of tuberculosis patients remains unclear. Tuberculosis immunopathology in the blood is characterised by patterns of immunosuppression and hyperinflammation. These seemingly contradictory findings and the pronounced heterogeneity made it difficult to interpret the results from previous studies and to derive implications of immunopathology. However, novel approaches based on comprehensive data analyses and revitalisation of an ancient plasma milieu in vitro assay connected inflammation with immunosuppressive factors in tuberculosis. Moreover, interrelations between the aberrant plasma milieu and immune cell pathology were observed. This review provides an overview of studies on changes in plasma milieu and discusses recent findings linking plasma factors to T-cell and monocyte/macrophage pathology in pulmonary tuberculosis patients.
Assuntos
Mycobacterium tuberculosis , Tuberculose Pulmonar , Humanos , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/patologia , Mycobacterium tuberculosis/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Linfócitos T/imunologia , Monócitos/imunologia , Interações Hospedeiro-Patógeno/imunologia , AnimaisRESUMO
Impaired T-cell responses to mitogens and high T-cell activation marker (TAM) expression on Mycobacterium tuberculosis-specific T-cells characterize immunopathology in patients with tuberculosis (TB). In a study of patients with TB (n = 60) and asymptomatic contacts (controls, n = 37), we found that TB patients had higher CD38+ T-cell proportions specific for M. tuberculosis protein (PPDMtb), yet total proportions of PPDMtb-specific T-cells were comparable. Notably, both activated (CD38+) and total IFN-γ+ T-cells from TB patients had lower mitogen (phytohemagglutinin, PHA)-induced responses. This impaired mitogen response improved the classification efficacy of the TAM-TB assay, especially employing the PPD/PHA-induced T-cell ratio.
Assuntos
Mycobacterium tuberculosis , Tuberculose , Humanos , Mitógenos/farmacologia , Tuberculina , Linfócitos T , Antígenos de BactériasRESUMO
BCG vaccination affects other diseases beyond tuberculosis by unknown-potentially immunomodulatory-mechanisms. Recent studies have shown that BCG vaccination administered during overt type 1 diabetes (T1D) improved glycemic control and affected immune and metabolic parameters. Here, we comprehensively characterized Ghanaian T1D patients with or without routine neonatal BCG vaccination to identify vaccine-associated alterations. Ghanaian long-term T1D patients (n = 108) and matched healthy controls (n = 214) were evaluated for disease-related clinical, metabolic, and immunophenotypic parameters and compared based on their neonatal BCG vaccination status. The majority of study participants were BCG-vaccinated at birth and no differences in vaccination rates were detected between the study groups. Notably, glycemic control metrics, i.e., HbA1c and IDAA1c, showed significantly lower levels in BCG-vaccinated as compared to unvaccinated patients. Immunophenotype comparisons identified higher expression of the T cell activation marker CD25 on CD8+ T cells from BCG-vaccinated T1D patients. Correlation analysis identified a negative correlation between HbA1c levels and CD25 expression on CD8+ T cells. In addition, we observed fractional increases in glycolysis metabolites (phosphoenolpyruvate and 2/3-phosphoglycerate) in BCG-vaccinated T1D patients. These results suggest that neonatal BCG vaccination is associated with better glycemic control and increased activation of CD8+ T cells in T1D patients.