RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Highlights from the Science family of journals.
RESUMO
Effective vaccines have reduced the morbidity and mortality caused by severe acute respiratory syndrome coronavirus-2 infection; however, the elderly remain the most at risk. Understanding how vaccines generate protective immunity and how these mechanisms change with age is key for informing future vaccine design. Cytotoxic CD8+ T cells are important for killing virally infected cells, and vaccines that induce antigen-specific CD8+ T cells in addition to humoral immunity provide an extra layer of immune protection. This is particularly important in cases where antibody titers are suboptimal, as can occur in older individuals. Here, we show that in aged mice, spike epitope-specific CD8+ T cells are generated in comparable numbers to younger animals after ChAdOx1 nCoV-19 vaccination, although phenotypic differences exist. This demonstrates that ChAdOx1 nCoV-19 elicits a good CD8+ T-cell response in older bodies, but that typical age-associated features are evident on these vaccine reactive T cells.
Assuntos
Linfócitos T CD8-Positivos , COVID-19 , Animais , Humanos , Camundongos , ChAdOx1 nCoV-19 , COVID-19/prevenção & controle , Vacinação , Linfócitos T Citotóxicos , Anticorpos AntiviraisRESUMO
Metabolic and nutrient-sensing pathways play an important role in controlling the efficacy of effector T cells. Oxygen is a critical regulator of cellular metabolism. However, during immune responses T cells must function in oxygen-deficient, or hypoxic, environments. Here, we used high resolution mass spectrometry to investigate how the proteome of primary murine CD8+ cytotoxic T lymphocytes (CTLs) is reconfigured in response to hypoxia in vitro. We identified and quantified over 7,600 proteins and discovered that hypoxia increased the abundance of a selected number of proteins in CTLs. This included glucose transporters, metabolic enzymes, transcription factors, cytolytic effector molecules, checkpoint receptors and adhesion molecules. While some of these proteins may augment the effector functions of CTLs, others may limit their cytotoxicity. Moreover, we determined that hypoxia could inhibit IL-2-induced proliferation cues and antigen-induced pro-inflammatory cytokine production in CTLs. These data provide a comprehensive resource for understanding the magnitude of the CTL response to hypoxia and emphasise the importance of oxygen-sensing pathways for controlling CD8+ T cells. Additionally, this study provides new understanding about how hypoxia may promote the effector function of CTLs, while contributing to their dysfunction in some contexts.
Assuntos
Hipóxia Celular , Proteoma , Linfócitos T Citotóxicos/metabolismo , Animais , Pontos de Checagem do Ciclo Celular , Hipóxia Celular/genética , Células Cultivadas , Cromatografia Líquida/métodos , Feminino , Regulação da Expressão Gênica , Ontologia Genética , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T , Interleucina-2/farmacologia , Lactatos/metabolismo , Espectrometria de Massas/métodos , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Anotação de Sequência Molecular , Biossíntese de Proteínas , Linfócitos T Citotóxicos/efeitos dos fármacosRESUMO
Personalized medicines require understanding the molecular causes of disease. In this issue of Immunity, Gruber et al. reveal that a gain-of-function JAK1 genetic variant results in a mutant protein with mosaic expression that drives multi-organ immune dysregulation via kinase dependent and independent mechanisms. The work highlights how biochemistry can inform therapies to resolve complex immune disorders.
Assuntos
Mosaicismo , Janus Quinase 1/genéticaRESUMO
Interleukin-2 (IL-2) and Janus kinases (JAKs) regulate transcriptional programs and protein synthesis to promote the differentiation of effector CD8+ cytotoxic T lymphocytes (CTLs). Using high-resolution mass spectrometry, we generated an in-depth characterization of how IL-2 and JAKs configure the CTL proteome to control CTL function. We found that IL-2 signaling through JAK1 and JAK3 (JAK1/3) increased the abundance of a key subset of proteins to induce the accumulation of critical cytokines and effector molecules in T cells. Moreover, IL-2 maintained the concentration of proteins that support core metabolic processes essential for cellular fitness. One fundamental insight was the dominant role for IL-2 in stimulating effector T cells to detect microenvironmental cues. IL-2-JAK1/3 signaling pathways thus increased the abundance of nutrient transporters, nutrient sensors, and critical oxygen-sensing molecules. These data provide key insights into how IL-2 promotes T cell function and highlight signaling mechanisms and transcription factors that integrate oxygen sensing to transcriptional control of CD8+ T cell differentiation.
