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Cross-reactive immune responses to SARS-CoV-2 have been observed in pre-pandemic cohorts and proposed to contribute to host protection. Here we assess 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV-2 exposure. Using a dual cytokine FLISpot assay on peripheral blood mononuclear cells, we enumerate the frequency of T cells specific for spike, nucleocapsid, membrane, envelope and ORF1 SARS-CoV-2 epitopes that cross-react with human endemic coronaviruses. We observe higher frequencies of cross-reactive (p = 0.0139), and nucleocapsid-specific (p = 0.0355) IL-2-secreting memory T cells in contacts who remained PCR-negative despite exposure (n = 26), when compared with those who convert to PCR-positive (n = 26); no significant difference in the frequency of responses to spike is observed, hinting at a limited protective function of spike-cross-reactive T cells. Our results are thus consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines. While cross-reactive immunity between human coronavirus and SARS-CoV-2 may contribute to host protection, validating evidences are still scarce. Here the authors assess a cohort of 52 donors with immediate-early contact with SARS-CoV-2 to correlate higher frequency of cross-reactive T cells with lower infection rate.

There is increasing evidence that lung-resident memory T and B cells play a critical role in protecting against respiratory reinfection. With a unique transcriptional and phenotypic profile, resident memory lymphocytes are maintained in a quiescent state, constantly surveying the lung for microbial intruders. Upon reactivation with cognate antigen, these cells provide rapid effector function to enhance immunity and prevent infection. Immunization strategies designed to induce their formation, alongside novel techniques enabling their detection, have the potential to accelerate and transform vaccine development. Despite most data originating from murine studies, this review will discuss recent insights into the generation, maintenance and characterisation of pulmonary resident memory lymphocytes in the context of respiratory infection and vaccination using recent findings from human and non-human primate studies.

Vaccination affords protection from disease by activating pathogen-specific immune cells and facilitating the development of persistent immunologic memory toward the vaccine-specific pathogen. Current vaccine regimens are often based on the efficiency of the acute immune response, and not necessarily on the generation of memory cells, in part because the mechanisms underlying the development of efficient immune memory remain incompletely understood. This Review describes recent advances in defining memory T cell metabolism and how metabolism of these cells might be altered in patients affected by mitochondrial diseases or metabolic syndrome, who show higher susceptibility to recurrent infections and higher rates of vaccine failure. It discusses how this new understanding could add to the way we think about immunologic memory, vaccine development, and cancer immunotherapy.

BackgroundPoorly immunogenic tumors are hardly responsive to immunotherapies such as immune checkpoint blockade (ICB) and are, therefore, a therapeutic challenge. Combination with other immunotherapies and/or immunogenic therapies, such as radiotherapy (RT), could make these tumors more immune responsive. We have previously shown that the immunocytokine L19–IL2 combined with single-dose RT resulted in 75% tumor remission and a 20% curative abscopal effect in the T cell-inflamed C51 colon carcinoma model. This treatment schedule was associated with the upregulation of inhibitory immune checkpoint (IC) molecules on tumor-infiltrating T cells, leading to only tumor growth delay in the poorly immunogenic Lewis lung carcinoma (LLC) model.MethodsWe aimed to trigger curative therapeutic responses in three tumor models (LLC, C51 and CT26) by “pushing the accelerator” of tumor immunity with L19–IL2 and/or “releasing the brakes” with ICB, such as antibodies directed against cytotoxic T lymphocyte associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), combined with single-dose RT (10 Gy or 5 Gy). Primary tumor endpoint was defined as time to reach four times the size of tumor volume at start of treatment (4T×SV). Multivariate analysis of 4T×SV was performed using the Cox proportional hazards model comparing each treatment group with controls. Causal involvement of T and natural killer (NK) cells in the anti-tumor effect was assessed by in vivo depletion of T, NK or both cell populations. Immune profiling was performed using flow cytometry on single cell suspensions from spleens, bone marrow, tumors and blood.ResultsCombining RT, anti-PD-L1 and L19–IL2 cured 38% of LLC tumors, which was both CD8+ T and NK cell dependent. LLC tumors were resistant to RT +anti-PD-L1 likely explained by the upregulation of other IC molecules and increased T regulatory cell tumor infiltration. RT+L19–IL2 outperformed RT+ICB in C51 tumors; effects were comparable in CT26 tumors. Triple combinations were not superior to RT+L19–IL2 in both these models.ConclusionsThis study demonstrated that combinatorial strategies rationally designed on biological effects can turn immunotherapy-resistant tumors into immunologically responsive tumors. This hypothesis is currently being tested in the international multicentric randomized phase 2 trial: ImmunoSABR (NCT03705403).

Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections 1 – 3 . Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4 – 11 ), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication–transcription complex (RTC) 12 , 13 , in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27 , a robust early innate signature of SARS-CoV-2 (ref. 14 ), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae . Seronegative healthcare workers with an innate signature of infection preferentially expand pre-existing T cells targeting the conserved replication transcription complex of SARS-CoV-2 in abortive infection.

Non-coding genetic variants may cause disease by modulating gene expression. However, identifying these expression quantitative trait loci (eQTLs) is complicated by differences in gene regulation across fluid functional cell states within cell types. These states—for example, neurotransmitter-driven programs in astrocytes or perivascular fibroblast differentiation—are obscured in eQTL studies that aggregate cells 1 , 2 . Here we modelled eQTLs at single-cell resolution in one complex cell type: memory T cells. Using more than 500,000 unstimulated memory T cells from 259 Peruvian individuals, we show that around one-third of 6,511 cis -eQTLs had effects that were mediated by continuous multimodally defined cell states, such as cytotoxicity and regulatory capacity. In some loci, independent eQTL variants had opposing cell-state relationships. Autoimmune variants were enriched in cell-state-dependent eQTLs, including risk variants for rheumatoid arthritis near ORMDL3 and CTLA4 ; this indicates that cell-state context is crucial to understanding potential eQTL pathogenicity. Moreover, continuous cell states explained more variation in eQTLs than did conventional discrete categories, such as CD4 + versus CD8 + , suggesting that modelling eQTLs and cell states at single-cell resolution can expand insight into gene regulation in functionally heterogeneous cell types. A single-cell Poisson model is used to analyse eQTLs in memory T cells across continuous, dynamic cell states, revealing that the cell context is critical to understanding variation in eQTLs and their association with disease.

T stem cell-like memory cells (T SCM cells) are considered to be essential for the maintenance of immune memory. The T SCM population has been shown to have the key properties of a stem cell population: multipotency, self-renewal and clonal longevity. Here we show that no single population has all these stem cell properties, instead the properties are distributed. We show that the human T SCM population consists of two distinct cell subpopulations which can be distinguished by the level of their CD95 expression (CD95int and CD95hi). Crucially, using long-term in vivo labelling of human volunteers, we establish that these are distinct populations rather than transient states of the same population. These two subpopulations have different functional profiles ex vivo , different transcriptional patterns, and different tissue distributions. They also have significantly different TREC content indicating different division histories and we find that the frequency of CD95hi T SCM increases with age. Most importantly, CD95hi and CD95int T SCM cells also have very different dynamics in vivo with CD95hi cells showing considerably higher proliferation but significantly reduced clonal longevity compared with CD95int T SCM . While both T SCM subpopulations exhibit considerable multipotency, no single population of T SCM cells has both the properties of self-renewal and clonal longevity. Instead, the “stemness” of the T SCM population is generated by the complementary dynamic properties of the two subpopulations: CD95int T SCM which have the property of clonal longevity and CD95hi T SCM which have the properties of expansion and self-renewal. We suggest that together, these two populations function as a stem cell population.

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 cells 3 . 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. Evidence of a transcriptional signature that marks precursors of long-lived CD8 + memory T cells in SARS-CoV-2 infection.

Rasmussen Encephalitis (RE) is a chronic, unilateral epileptic disorder mostly found in children. Neuropathologically, it is characterized by T lymphocyte infiltration targeting neurons and leading to microglia activation, astrogliosis, and cortical degeneration. Within a patient’s brain, distinct pathological stages are found that offer a unique opportunity to study T cell dynamics in situ. Using quantitative multiplex fluorescence imaging, we analyzed CD103 + and CD69 + Tissue-resident memory T cells (T RM ) across different disease stages. This analysis revealed that T RM were more abundant in the parenchyma than in the perivascular space, suggesting that their differentiation occurs locally after antigen encounter. Further, part of the T RM expressed Granzyme-B (GrB) and frequently were attached to neurons, suggesting that they are actively involved in neuronal destruction. While T RM showed a stage-dependent increase in older lesions, the proportions of these cells did not correlate with disease duration, indicating that their accumulation may be more dependent on the local environment in the lesion than on the length of the disease. In addition, we found that T cells using the γδ T cell receptor comprised up to 66%. Like CD8 + T cells, the γδ T cells could develop a T RM phenotype and, while expressing GrB + granules, they were seen attached to neurons, suggesting that they are involved in neuronal destruction. Finally, analysis of exhaustion- and T RM -associated immune checkpoint control markers PD-1 and LAG-3 revealed a significant stage-dependent increase in PD-1 expression in the oldest lesions. In contrast, LAG-3 expression did not show any stage-specific pattern, pointing towards a distinct regulatory mechanism. The study demonstrates a dynamic and one-way T cell response throughout the course of RE at a given spot in the CNS: from the establishment of T cell residence after entry into the CNS, the killing of neurons, and eventually T cell exhaustion. It further suggests an important role of γδ T-cells in the propagation of disease and lesions.

BACKGROUNDNaive cells comprise 90% of the CD4+ T cell population in neonates and exhibit distinct age-specific capacities for proliferation and activation. We hypothesized that HIV-infected naive CD4+ T cell populations in children on long-term antiretroviral therapy (ART) would thus be distinct from infected memory cells.METHODSPeripheral blood naive and memory CD4+ T cells from 8 children with perinatal HIV on ART initiated at age 1.7-17 months were isolated by FACS. DNA was extracted from sorted cells, and HIV proviruses were counted, evaluated for intactness, and subjected to integration site analysis (ISA).RESULTSNaive CD4+ T cells containing HIV proviruses were detected in children with 95% statistical confidence. A median 4.7% of long terminal repeat-containing naive CD4+ T cells also contained HIV genetic elements consistent with intactness. Full-length proviral sequencing confirmed intactness of 1 provirus. In the participant with the greatest degree of naive cell infection, ISA revealed infected expanded cell clones in both naive and memory T cells, with no common HIV integration sites detected between subsets. Divergent integration site profiles reflected differential gene expression patterns of naive and memory T cells.CONCLUSIONThese results demonstrate that HIV persisted in both naive and memory CD4+ T cells that underwent clonal expansion and harbored intact proviruses, and suggest that infected memory T cell clones do not frequently arise from naive cell differentiation in children with perinatal HIV on long-term ART.FUNDINGCenter for Cancer Research, NCI; Office of AIDS Research; NCI FLEX; Children's and Emory Junior Faculty Focused Award.