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Signature of long-lived memory CD8⁺ T cells in acute SARS-CoV-2 infection.

ABSTRACT: Immunological memory is a hallmark of adaptive immunity and facilitates an accelerated and enhanced immune response upon re-infection with the same pathogen^1,2. 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.

SUBMITTER: Adamo S

PROVIDER: S-EPMC8810382 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Signature of long-lived memory CD8+ T cells in acute SARS-CoV-2 infection.

Adamo Sarah S Michler Jan J Zurbuchen Yves Y Cervia Carlo C Taeschler Patrick P Raeber Miro E ME Baghai Sain Simona S Nilsson Jakob J Moor Andreas E AE Boyman Onur O

Nature 20211207 7895

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 long ...[more]

PMID: 34875673

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Project description:BackgroundThe immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in COVID-19 patients has been extensively investigated. However, much less is known about the long-term effects of infection in patients and how it could affect the immune system and its capacity to respond to future perturbations.MethodsUsing a targeted single-cell multiomics approach, we have recently identified a prolonged anti-inflammatory gene expression signature in T and NK cells in type 1 diabetes patients treated with low-dose IL-2. Here, we investigated the dynamics of this signature in three independent cohorts of COVID-19 patients: (i) the Oxford COVID-19 Multi-omics Blood Atlas (COMBAT) dataset, a cross-sectional cohort including 77 COVID-19 patients and ten healthy donors; (ii) the INCOV dataset, consisting of 525 samples taken from 209 COVID-19 patients during and after infection; and (iii) a longitudinal dataset consisting of 269 whole-blood samples taken from 139 COVID-19 patients followed for a period of up to 7 months after the onset of symptoms using a bulk transcriptomic approach.ResultsWe discovered that SARS-CoV-2 infection leads to a prolonged alteration of the gene expression profile of circulating T, B and NK cells and monocytes. Some of the genes affected were the same as those present in the IL-2-induced anti-inflammatory gene expression signature but were regulated in the opposite direction, implying a pro-inflammatory status. The altered transcriptional profile was detected in COVID-19 patients for at least 2 months after the onset of the disease symptoms but was not observed in response to influenza infection or sepsis. Gene network analysis suggested a central role for the transcriptional factor NF-κB in the regulation of the observed transcriptional alterations.ConclusionsSARS-CoV-2 infection causes a prolonged increase in the pro-inflammatory transcriptional status that could predispose post-acute patients to the development of long-term health consequences, including autoimmune disease, reactivation of other viruses and disruption of the host immune system-microbiome ecosystem.

Project description:Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogens, but also have many properties in common with naive cells, including pluripotency and the ability to migrate to the lymph nodes and spleen. Thus, memory cells embody features of both naive and effector cells, fuelling a long-standing debate centred on whether memory T cells develop from effector cells or directly from naive cells. Here we show that long-lived memory CD8 T cells are derived from a subset of effector T cells through a process of dedifferentiation. To assess the developmental origin of memory CD8 T cells, we investigated changes in DNA methylation programming at naive and effector cell-associated genes in virus-specific CD8 T cells during acute lymphocytic choriomeningitis virus infection in mice. Methylation profiling of terminal effector versus memory-precursor CD8 T cell subsets showed that, rather than retaining a naive epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naive-associated genes and became demethylated at the loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase Dnmt3a at an early stage of effector differentiation resulted in reduced methylation and faster re-expression of naive-associated genes, thereby accelerating the development of memory cells. Longitudinal phenotypic and epigenetic characterization of the memory-precursor effector subset of virus-specific CD8 T cells transferred into antigen-free mice revealed that differentiation to memory cells was coupled to erasure of de novo methylation programs and re-expression of naive-associated genes. Thus, epigenetic repression of naive-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells while key effector genes remain demethylated, demonstrating that memory T cells arise from a subset of fate-permissive effector T cells.

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Signature of long-lived memory CD8⁺ T cells in acute SARS-CoV-2 infection.

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Signature of long-lived memory CD8<sup>+</sup> T cells in acute SARS-CoV-2 infection.

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