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During human CMV infection, there is a preferential expansion of natural killer (NK) cells expressing the activating CD94–NKG2C receptor complex, implicating this receptor in the recognition of CMV-infected cells. We hypothesized that NK cells expanded in response to pathogens will be marked by expression of CD57, a carbohydrate antigen expressed on highly mature cells within the CD56dimCD16+ NK cell compartment. Here we demonstrate the preferential expansion of a unique subset of NK cells coexpressing the activating CD94–NKG2C receptor and CD57 in CMV+ donors. These CD57+NKG2Chi NK cells degranulated in response to stimulation through their NKG2C receptor. Furthermore, CD57+NKG2Chi NK cells preferentially lack expression of the inhibitory NKG2A receptor and the inhibitory KIR3DL1 receptor in individuals expressing its HLA-Bw4 ligand. Moreover, in solid-organ transplant recipients with active CMV infection, the percentage of CD57+NKG2Chi NK cells in the total NK cell population preferentially increased. During acute CMV infection, the NKG2C+ NK cells proliferated, became NKG2Chi, and finally acquired CD57. Thus, we propose that CD57 might provide a marker of \"memory\" NK cells that have been expanded in response to infection.

New HIV vaccine approaches are focused on eliciting broadly neutralizing antibodies. We characterized early gamma-delta (γδ) T cell responses starting from pre-acquisition and during acute HIV infection (AHI) in participants previously characterized for neutralization breadth development. We found significant differences in γδ T cell surface marker expression in participants that developed neutralization breadth compared to those that did not. Activation of γδ T cells occurred within the first weeks of HIV acquisition and associated with viral load. Expression of CD16 on Vδ1 T cells and CD57 on Vδ2 T cells were found to be significantly higher in broad neutralizers during AHI, and associated with the development of neutralization breadth years later. In addition, the levels of CD16 on Vδ1 T cells was associated with early production of founder virus Env-specific IgM. Thus, γδ T cells may promote development of neutralization breadth, which has implications for HIV vaccine strategies.

Key Points T cells exposed to persistent antigen and/or inflammatory signals in chronic infection or cancer can become 'exhausted', a state characterized by a hierarchical loss of effector functions and memory T cell properties, and by the expression of multiple inhibitory receptors. T cell exhaustion prevents optimal control of infections and tumours, but modulating inhibitory pathways that are overexpressed in exhaustion can reverse this dysfunctional state and reinvigorate immune responses. Exhausted T cells are a distinct lineage of differentiated T cells; these cells are phenotypically and mechanistically different from other dysfunctional states of T cells such as anergy and senescence. Altered usage of transcription factors is a key feature of T cell exhaustion. Whereas transcription factors such as T-bet, EOMES (eomesodermin) and BLIMP1 (B lymphocyte-induced maturation protein 1) can have roles in other T cell populations, their expression pattern, target genes and functions in exhausted T cells are distinct. Antigen-specific CD4 + T cells also progress to exhaustion during chronic infection. Although CD4 + and CD8 + T cell exhaustion share a core transcriptional signature, exhaustion of CD4 + T cells is distinct from that of CD8 + T cells, as each subset has different expression patterns of molecules such as inhibitory receptors and transcription factors. Exhausted T cells display a phenotype characterized by progressive loss of function, and they can develop following exposure to persistent antigen and/or inflammatory signals during chronic viral infections or cancer. The authors describe the molecular mechanisms of T cell exhaustion and how the exhausted phenotype is different from other dysfunctional states of T cells. In chronic infections and cancer, T cells are exposed to persistent antigen and/or inflammatory signals. This scenario is often associated with the deterioration of T cell function: a state called 'exhaustion'. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme. T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity. Here, we review recent advances that provide a clearer molecular understanding of T cell exhaustion and reveal new therapeutic targets for persisting infections and cancer.

Common variable immunodeficiency (CVID) is associated with an altered immune homeostasis affecting many T-cell subpopulations, including an increased proportion of CD57 CD8 T lymphocytes. This expansion has been associated with the clinical manifestation of granuloma/lymphadenopathy and a positive CMV status. The aim of the study is to describe the prevalence of an expansion of CD57 CD8 T cells in CVID patients and determine its diagnostic value. This is a monocentric retrospective study including 131 patients with a median follow-up of 9 years. The inclusion criteria are a diagnosis of CVID according to European Society for Immunodeficiencies (ESID) criteria and at least two independent assessments of CD57 CD8 T cells. Patients on immunosuppressive therapy were excluded. The expansion of CD57 CD8 T cells was part of the previously described immune alteration, including altered CD4/CD8 ratio and a decrease in naïve CD4 T cells. The loss of significant association with increasing age might corroborate the suggestion of premature immunosenescence in CVID. Significantly higher values of CD57 CD8 T cells were seen in patients with a complicated clinical phenotype, and especially associated with the presence of splenomegaly, status post-splenectomy, and hepatic disease. Additionally, patients with a history of CMV infection presented with elevated CD57 CD8 T cell values. When comparing the potential diagnostic value of expanded CD57 CD8 T cells compared to alterations in other T-cell subsets in relation to specific complications, we could not identify a single complication in CVID patients for which absolute or relative CD57 CD8 T cell counts were superior to more commonly used T-cell populations, except for CMV infection. This is the largest study on the prevalence and diagnostic relevance of the expansion of CD57 CD8 T cells in CVID. Most CD57 CD8 T cells are part of the CD45RA terminal effector subset. While we could not detect an added value of the diagnostic evaluation of CD57 CD8 T cells at this time, further investigation in circulation and tissue might enhance our understanding of the pathogenesis of hepatic disease and thereby gain novel diagnostic value in the future.

Herpes simplex virus (HSV)-specific CD8+ T cells protect mice from herpes infection and disease. However, the phenotype and function of HSV-specific CD8+ T cells that play a key role in the “natural” protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) patients (who have never had clinical herpes disease) remain to be determined. We previously reported that symptomatic (SYMP) patients (who have frequent bouts of recurrent ocular herpes disease) had more undifferentiated and dysfunctional HSV-specific CD8+ T cells. In contrast, healthy ASYMP individuals maintained a significantly higher proportion of differentiated polyfunctional CD8+ T cells. Here, we report that HSV-specific CD8+ T cells from 10 SYMP patients, but not HSV-specific CD8+ T cells from 10 ASYMP patients, have phenotypic and functional characteristics of cellular senescence, including: (i) high frequency of senescent (CD57+) and exhausted (PD-1+) CD8+ T cells; (ii) late terminally differentiated (KLRG1+), non-proliferating CD8+ T cells; (iii) HSV-specific CD8+ T cells which decreased in number over time and were not homeostatically maintained, as indicated by a reduction in the number of CD127+CD8+ T cells; (iv) loss of the co-stimulatory molecule CD28 on HSV-specific CD8+ T cells; and (v) decreased production of effector molecules (granzyme B and perforin) by HSV-specific CD8+ T cells. Our findings provide insights into the role of senescence in HSV-specific CD8+ T cells in susceptibility to recurrent herpes and have implications for T-cell-based immunotherapeutic strategies against recurrent herpes in humans.

Kaposi's sarcoma herpesvirus (KSHV) remains the most common opportunistic malignancy that contributes to morbidity and mortality among persons living with HIV (PLWH) worldwide. The immune response in PLWH can exhibit signs of functional exhaustion, characterized by CD57 expression and mitochondrial dysfunction in T-cells. Valganciclovir (VGC), as an add-on therapy in patients with disseminated Kaposi Sarcoma/human immunodeficiency virus (DKS/HIV), modulates the activation of T-cell subsets; however, its effect on the T-cell immunosenescence profile is unclear. This study evaluated the T-cell immunosenescence profile in DKS/HIV patients who received two treatment schedules: A group received antiretroviral therapy (cART) as conventional therapy (CT, n=10), while a second group received an experimental regimen, consisting of VGC initially plus cART (VGC+cART, n=10) by the fourth week. Mononuclear cells from DKS/HIV patients were obtained at baseline (W ) and at weeks W and W of treatment. T-cells were labeled with cell markers such as CD3, CD4, CD8, CD27, CD57, KLRG1, PD-1, TIM-3, and GLUT1, as well as soluble molecules and a proteome profile array of proteins related to proteases. Data showed that DKS/HIV patients have an increased frequency of GLUT1+ T-cells at diagnosis, which was not modified after treatment initiation. The presence of CD8+CD57+KLRG1+ T-cells was expanded in DKS/HIV patients and maintained across follow-up once VGC+cART treatment was started. Although DKS/HIV patients display high plasma levels of soluble ligands for KLRG1 (E-cadherin) and TIM-3 (Gal-9) at diagnosis, together with proteases associated with the regulation of T-cells and the induction of T-cell immunosenescence, both treatment schedules reduce their soluble levels after 12 weeks of follow-up. The microenvironment generated in DKS/HIV patients increases the frequency of T-cells exhibiting an immunosenescence phenotype, and this effect is independent of the treatment schedule used, suggesting that during coinfection, a chronic immunosuppressive microenvironment may develop, impairing immune surveillance and resilience. These results could be explored to identify novel therapeutic approaches.

The CD57 antigen (alternatively HNK-1, LEU-7, or L2) is routinely used to identify terminally differentiated ‘senescent’ cells with reduced proliferative capacity and altered functional properties. In this article, we review current understanding of the attributes of CD57-expressing T-cells and NK cells in both health and disease and discuss how this marker can inform researchers about their likely functions in human blood and tissues in vivo. While CD57 expression on human lymphocytes indicates an inability to proliferate, these cells also display high cytotoxic potential, and CD57 pos NK cells exhibit both memory-like features and potent effector functions. Accordingly, frequencies of CD57-expressing cells in blood and tissues have been correlated with clinical prognosis in chronic infections or various cancers and with human aging. Functional modulation of senescent CD57 pos T-cells and mature CD57 pos NK cells may therefore represent innovative strategies for protection against human immunological aging and/or various chronic diseases.

Although T cells are known to be involved in the pathogenesis of coronary artery disease, it is unclear which subpopulation of T cells contributes to pathogenesis in acute myocardial infarction (MI). We studied the immunological characteristics and clinical impact of CD8 + CD57 + T cells in acute MI patients. The frequency of CD57 + cells among CD8 + T cells was examined in peripheral blood sampled the morning after acute MI events. Interestingly, the frequency of CD57 + cells in the CD8 + T-cell population correlated with cardiovascular mortality 6 months after acute MI. The immunological characteristics of CD8 + CD57 + T cells were elucidated by surface immunophenotyping, intracellular cytokine staining and flow cytometry. Immunophenotyping revealed that the CD8 + CD57 + T cells were activated, senescent T cells with pro-inflammatory and tissue homing properties. Because a high frequency of CD8 + CD57 + T cells is associated with short-term cardiovascular mortality in acute MI patients, this specific subset of CD8 + T cells might contribute to acute coronary events via their pro-inflammatory and high cytotoxic capacities. Identification of a pathogenic CD8 + T-cell subset expressing CD57 may offer opportunities for the evaluation and management of acute MI.

Tumor-infiltrating natural killer (NK) cells (TINKs) are crucial immune cells in tumor defense, and might be related to tumor prognosis. However, the results were discrepant among different studies. The present meta-analysis was performed to comprehensively assess the prognostic value of NK cell markers in solid tumor tissues. PubMed, Web of Science, and EMBASE were searched to identify original researches reporting the prognostic significance of TINKs in solid tumors. NK cell markers CD56, CD57, NKp30, and NKp46 were included in the analysis. The hazard ratios (HRs) and 95% confidence intervals (CIs) of pooled overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), progression-free survival (PFS), and recurrence-free survival (RFS) were calculated by STATA software 14.0 to assess the prognostic significance. Of the 56 included studies, there were 18 studies on CD56, 31 studies on CD57, 1 study on NKp30, and 7 studies on NKp46. High levels of CD56, CD57, NKp30, and NKp46 were significantly correlated with better OS of patients with solid malignancies (HR = 0.473, 95%CI: 0.315-0.710, < 0.001; HR = 0.484, 95%CI: 0.380-0.616, < 0.001; HR = 0.34, 95%CI: 0.14-0.80, = 0.014; HR = 0.622, 95%CI: 0.470-0.821, < 0.001, respectively). Our results also revealed that CD56, CD57, and NKp46 could act as independent prognostic predictors for favorable OS (HR = 0.372, 95%CI: 0.261-0.531, < 0.001; HR = 0.525, 95%CI: 0.346-0.797, = 0.003; HR = 0.559, 95%CI: 0.385-0.812, = 0.002, respectively). Our results indicated that high levels of NK cell markers in solid tumor tissues could predict favorable prognosis for solid tumor patients.

Adaptive human natural killer (NK) cells are an NK cell subpopulation arising upon cytomegalovirus (CMV) infection. They are characterized by CD94/NKG2C expression, a mature CD57 KIR NKG2A phenotype, a prolonged lifespan, and remarkable antitumor functions. In light of these features, adaptive NK cells represent suitable candidate to design next-generation therapies, based on their enhanced effector function which could be further boosted by Chimeric Antigen Receptors-engineering, or the combination with cell engagers. For therapeutic approaches, however, it is key to generate large numbers of functional cells. We developed a method to efficiently expand adaptive NK cells from NK-enriched cell preparations derived from the peripheral blood of selected CMV-seropositive healthy donors. The method is based on the use of an anti-CD94 monoclonal antibody (mAb) combined with IL-2 or IL-15. By setting this method we were able to expand high numbers of NK cells showing the typical adaptive phenotype, CD94/NKG2C CD94/NKG2A CD57 , and expressing a single self-inhibitory KIR. Expanded cells maintained the CMV-induced molecular signature, exhibited high ADCC capabilities and degranulation against a HLA-E target. Importantly, mAb-expanded adaptive NK cells did not upregulate PD-1 or other regulatory immune checkpoints that could dampen their function. By this study we provide hints to improve previous expansion methods, by eliminating the use of genetically modified cells as stimulators, and obtaining effectors not expressing unwanted inhibitory receptors. This new protocol for expanding functional adaptive NK cells is safe, cost-effective and easily implementable in a GMP context, suitable for innovative immunotherapeutic purposes.