RESUMO
Patients with activated phosphatidylinositol 3-kinase delta (PI3Kδ) syndrome (APDS) present with sinopulmonary infections, lymphadenopathy, and cytomegalvirus (CMV) and/or Epstein-Barr virus (EBV) viremia, yet why patients fail to clear certain chronic viral infections remains incompletely understood. Using patient samples and a mouse model (Pik3cdE1020K/+ mice), we demonstrate that, upon activation, Pik3cdE1020K/+ CD8+ T cells exhibit exaggerated features of effector populations both in vitro and after viral infection that are associated with increased Fas-mediated apoptosis due to sustained FoxO1 phosphorylation and Fasl derepression, enhanced mTORC1 and c-Myc signatures, metabolic perturbations, and an altered chromatin landscape. Conversely, Pik3cdE1020K/+ CD8+ cells fail to sustain expression of proteins critical for central memory, including TCF1. Strikingly, activated Pik3cdE1020K/+ CD8+ cells exhibit altered transcriptional and epigenetic circuits characterized by pronounced interleukin-2 (IL-2)/STAT5 signatures and heightened IL-2 responses that prevent differentiation to memory-like cells in IL-15. Our data position PI3Kδ as integrating multiple signaling nodes that promote CD8+ T cell effector differentiation, providing insight into phenotypes of patients with APDS.
Assuntos
Linfócitos T CD8-Positivos/enzimologia , Montagem e Desmontagem da Cromatina , Cromatina/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Memória Imunológica , Doenças da Imunodeficiência Primária/enzimologia , Transcrição Gênica , Viroses/enzimologia , Adolescente , Adulto , Animais , Apoptose , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Estudos de Casos e Controles , Criança , Cromatina/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Modelos Animais de Doenças , Ativação Enzimática , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia , Transdução de Sinais , Viroses/genética , Viroses/imunologiaRESUMO
Progenitor-like CD8+ T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8+ T cells responding to acute and chronic viral infections, we found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8+ T cells and was required for the programming of progenitor-like CD8+ T cells. Thus, long-term CD8+ T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Infecções/etiologia , Análise de Célula Única , Animais , Biomarcadores , Imunoprecipitação da Cromatina , Epigênese Genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Memória Imunológica , Infecções/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Fatores de Tempo , TranscriptomaRESUMO
Gain-of-function mutations in the gene encoding the phosphatidylinositol-3-OH kinase catalytic subunit p110δ (PI3Kδ) result in a human primary immunodeficiency characterized by lymphoproliferation, respiratory infections and inefficient responses to vaccines. However, what promotes these immunological disturbances at the cellular and molecular level remains unknown. We generated a mouse model that recapitulated major features of this disease and used this model and patient samples to probe how hyperactive PI3Kδ fosters aberrant humoral immunity. We found that mutant PI3Kδ led to co-stimulatory receptor ICOS-independent increases in the abundance of follicular helper T cells (TFH cells) and germinal-center (GC) B cells, disorganized GCs and poor class-switched antigen-specific responses to immunization, associated with altered regulation of the transcription factor FOXO1 and pro-apoptotic and anti-apoptotic members of the BCL-2 family. Notably, aberrant responses were accompanied by increased reactivity to gut bacteria and a broad increase in autoantibodies that were dependent on stimulation by commensal microbes. Our findings suggest that proper regulation of PI3Kδ is critical for ensuring optimal host-protective humoral immunity despite tonic stimulation from the commensal microbiome.
Assuntos
Linfócitos B/fisiologia , Microbioma Gastrointestinal/imunologia , Centro Germinativo/fisiologia , Mutação/genética , Fosfatidilinositol 3-Quinases/genética , Linfócitos T Auxiliares-Indutores/fisiologia , Animais , Autoanticorpos/sangue , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/genética , Modelos Animais de Doenças , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Imunidade Humoral/genética , Switching de Imunoglobulina/genética , Síndromes de Imunodeficiência/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
GA binding protein (GABP) is a ubiquitously expressed Ets-family transcription factor that critically regulates the expression of the interleukin-7 receptor alpha chain (IL-7Ralpha) in T cells, whereas it is dispensable for IL-7Ralpha expression in fetal liver B cells. Here we showed that deficiency of GABPalpha, the DNA-binding subunit of GABP, resulted in profoundly defective B cell development and a compromised humoral immune response, in addition to thymic developmental defects. Furthermore, the expression of Pax5 and Pax5 target genes such as Cd79a was greatly diminished in GABPalpha-deficient B cell progenitors, pro-B, and mature B cells. GABP could bind to the regulatory regions of Pax5 and Cd79a in vivo. Thus, GABP is a key regulator of B cell development, maturation, and function.