RESUMEN
Immunological memory is a hallmark of adaptive immunity and facilitates an accelerated and enhanced immune response upon re-infection with the same pathogen1,2. Since the outbreak of the ongoing COVID-19 pandemic, a key question has focused on which SARS-CoV-2-specific T cells stimulated during acute infection give rise to long-lived memory T cells3. Here, using spectral flow cytometry combined with cellular indexing of transcriptomes and T cell receptor sequencing, we longitudinally characterized individual SARS-CoV-2-specific CD8+ T cells of patients with COVID-19 from acute infection to 1 year into recovery and found a distinct signature identifying long-lived memory CD8+ T cells. SARS-CoV-2-specific memory CD8+ T cells persisting 1 year after acute infection express CD45RA, IL-7 receptor-α and T cell factor 1, but they maintain low expression of CCR7, thus resembling CD45RA+ effector memory T cells. Tracking individual clones of SARS-CoV-2-specific CD8+ T cells, we reveal that an interferon signature marks clones that give rise to long-lived cells, whereas prolonged proliferation and mechanistic target of rapamycin signalling are associated with clonal disappearance from the blood. Collectively, we describe a transcriptional signature that marks long-lived, circulating human memory CD8+ T cells following an acute viral infection.
Asunto(s)
Antígenos Virales/inmunología , Biomarcadores/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , COVID-19/inmunología , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , SARS-CoV-2/inmunología , Enfermedad Aguda , COVID-19/virología , Proliferación Celular , Células Clonales/citología , Células Clonales/inmunología , Humanos , Interferones/inmunología , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Estudios Longitudinales , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores CCR7/metabolismo , Factor 1 de Transcripción de Linfocitos T/metabolismo , Factores de Tiempo , TranscriptomaRESUMEN
The transcription factor T cell factor 1 (TCF1), a pioneer transcription factor as well as a downstream effector of WNT/ß-catenin signaling, is indispensable for T cell development in the thymus. Recent studies have highlighted the additional critical role of TCF1 in peripheral T cell responses to acute and chronic infections as well as cancer. Here, we review the regulatory functions of TCF1 in the differentiation of T follicular helper cells, memory T cells and recently described stem-like exhausted T cells, where TCF1 promotes less differentiated stem-like cell states by controlling common gene-regulatory networks. These studies also provide insights into the mechanisms of defective T cell responses in older individuals. We discuss alterations in TCF1 expression and related regulatory networks with age and their consequences for T cell responses to infections and vaccination. The increasing understanding of the pathways regulating TCF1 expression and function in aged T cells holds the promise of enabling the design of therapeutic interventions aiming at improving T cell responses in older individuals.