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Human Immunodeficiency Virus (HIV) has plagued human society for a long time since its discovery, causing a large number of patients to suffer and costing hundreds of millions of medical services every year. Scientists have found that HIV and antiretroviral therapy accelerate immune aging by inducing mitochondrial dysfunction, and that terminal effector memory T cells (TEMRA cells) are crucial in immune aging. This specific subset of effector memory T cells has terminally differentiated properties and exhibits high cytotoxicity and proinflammatory capacity. We therefore explored and described the interplay between exhaustion features, essential markers, functions, and signaling pathways from previous studies on HIV, antiretroviral therapy, immune senescence, and TEMRA cells. Their remarkable antiviral capacity is then highlighted by elucidating phenotypic changes in TEMRA cells during HIV infection, describing changes in TEMRA cells before, during, and after antiretroviral therapy and other drug treatments. Their critical role in complications and cytomegalovirus (CMV)-HIV superinfection is highlighted. These studies demonstrate that TEMRA cells play a key role in the antiviral response and immune senescence during HIV infection. Finally, we review current therapeutic strategies targeting TEMRA cells that may be clinically beneficial, highlight their potential role in HIV-1 vaccine development, and provide perspectives and predictions for related future applications.

Background Alzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. Methods We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). Results We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1 + CD57 + CD8 + T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Conclusions Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology. Highlights • Peripheral CD8 + TEMRA cells expressing markers associated with senescence accumulate in AD patients before dementia onset. • Peripheral immune cells correlate with AD biomarkers, varying by clinical AD stage. • APOE ε4 modifies peripheral immunity and its association with clinical AD measures.

Background Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing–remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS. Methods Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively. Results Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + T EMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy. Conclusions Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + T EMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.

A major challenge after allogeneic haematopoietic stem cell transplantation for haematologic malignancies is the management of acute graft-versus-host disease (aGVHD), which remains associated with poor prognosis despite therapeutic advancements. We conducted a randomized, double-blinded, placebo-controlled Phase I/II clinical trial to assess the safety and efficacy of umbilical cord-derived mesenchymal stem cells (Cyto-MSC) as an upfront treatment in patients with grade II-IV aGVHD.BackgroundA major challenge after allogeneic haematopoietic stem cell transplantation for haematologic malignancies is the management of acute graft-versus-host disease (aGVHD), which remains associated with poor prognosis despite therapeutic advancements. We conducted a randomized, double-blinded, placebo-controlled Phase I/II clinical trial to assess the safety and efficacy of umbilical cord-derived mesenchymal stem cells (Cyto-MSC) as an upfront treatment in patients with grade II-IV aGVHD.In this multicentre trial, 22 grade II-IV aGVHD patients were randomized to receive up to three infusions of Cyto-MSC (n = 14) or placebo (n = 8), alongside standard corticosteroid therapy. The primary endpoints were overall response (OR) at Day 28 and overall survival (OS) at 12 months. The secondary endpoints included correlation between responses at Day 28 with 12-month OS and exploratory analyses of immune cell subsets.MethodsIn this multicentre trial, 22 grade II-IV aGVHD patients were randomized to receive up to three infusions of Cyto-MSC (n = 14) or placebo (n = 8), alongside standard corticosteroid therapy. The primary endpoints were overall response (OR) at Day 28 and overall survival (OS) at 12 months. The secondary endpoints included correlation between responses at Day 28 with 12-month OS and exploratory analyses of immune cell subsets.No treatment-related adverse events were observed. There were no significant differences between Cyto-MSC and placebo in the OR at Day 28 and 12-month OS. Among patients with severe grade III-IV aGVHD who achieved OR by Day 28, those treated with Cyto-MSC had significantly improved 12-month OS compared to placebo (100% vs 50%, p=0.039). Furthermore, in patients with severe aGVHD and baseline CD4+ TEMRA >35% or CD8+ TEMRA >70%, the survival benefit was pronounced in the Cyto-MSC group (83.3% and 100%, respectively). In contrast, none of the placebo-treated patients with baseline CD4+ TEMRA <35% (p=0.007) or CD8+ TEMRA <70% (p=0.005) survived at 12 months. OS was significantly associated with OR at Day 28 (p<0.001), baseline CD4⁺ TEMRA (p=0.004), and baseline CD8⁺ TEMRA (p=0.004).ResultsNo treatment-related adverse events were observed. There were no significant differences between Cyto-MSC and placebo in the OR at Day 28 and 12-month OS. Among patients with severe grade III-IV aGVHD who achieved OR by Day 28, those treated with Cyto-MSC had significantly improved 12-month OS compared to placebo (100% vs 50%, p=0.039). Furthermore, in patients with severe aGVHD and baseline CD4+ TEMRA >35% or CD8+ TEMRA >70%, the survival benefit was pronounced in the Cyto-MSC group (83.3% and 100%, respectively). In contrast, none of the placebo-treated patients with baseline CD4+ TEMRA <35% (p=0.007) or CD8+ TEMRA <70% (p=0.005) survived at 12 months. OS was significantly associated with OR at Day 28 (p<0.001), baseline CD4⁺ TEMRA (p=0.004), and baseline CD8⁺ TEMRA (p=0.004).Patients with severe grade III-IV aGVHD, particularly those who respond early or have elevated baseline CD4+ TEMRA (>35%) or CD8+ TEMRA (>70%) levels, may have an overall survival advantage when treated with Cyto-MSC as an upfront therapy in combination with standard corticosteroids.ConclusionPatients with severe grade III-IV aGVHD, particularly those who respond early or have elevated baseline CD4+ TEMRA (>35%) or CD8+ TEMRA (>70%) levels, may have an overall survival advantage when treated with Cyto-MSC as an upfront therapy in combination with standard corticosteroids.

CD8+ T cells are commonly viewed as pro-inflammatory cytotoxic T lymphocytes (CTLs) even though immune-suppressive CD8+ regulatory T cells (CD8+ Tregs) have been described for over a half centenary [6]. [...]it is understandable to conjecture that these disease-associated CD8+ T cells elicit immune responses and inflict cytotoxicity in the central nervous system (CNS) resulting in neurodegeneration [3, 4]. TCR Vβ repertoire analysis in MS patients shows that clonally expanded CD8+ T cells in MS lesions in the brain are reflected in peripheral blood and CSF, particularly, in CSF [10]. [...]analyzing clonally expanded CD8+ T cells in CSF, which is much more feasible than analyzing the sparse brain infiltrating T cells, is a valuable approach to study the role of T cells in neurodegenerative diseases. CD45RA is a naïve T cell marker, but TEMRA cells regain the expression of CD45RA while maintaining the CD27−CCR7− cell surface marker characteristic of effector memory cells. [...]TEMRA cells are conventionally defined as CD45RA+CD27−, CD45RA+CCR7−, or CD45RA+ CD27−CCR7− T cells, which can be readily identified with flow cytometric analysis using fluorescent-conjugated antibodies specific for CD45RA, CD27 or CCR7. scRNA-seq analysis does not usually distinguish the RA and RO isoforms of CD45, and TEMRA cells are defined as memory (CD27−CCR7−) T cells expressing high levels of TEMRA-associated genes such as GZMA (granzyme A), GZMB (granzyme B), PRF1 (perforin) and NKG7 [5]. [...]KIR+CD8+ T cells are shown to specifically kill activated pathogenic or autoreactive CD4+ T cells acting as immune-suppressive regulatory T cells [8]. [...]unlike conventional TEMRA cells that are terminally differentiated with poor proliferative capacity, CD161−CD56+ CD8+ Tregs proliferate robustly and maintain their functional characteristics after long-term culturing [11, 12].

Chronic kidney failure (KF) provokes the development of immune senescent CD8 + cytotoxic T cells, affecting the occurrence of graft rejection, viral infections, and malignancies after kidney transplantation. In this study, we analyzed the impact of KF, subsequent dialysis treatment, and kidney transplantation on the differentiation of CD8 + CD31 + CD45RA + CCR7 + recent thymic emigrant (CCR7 + RTE) Tregs/Tresps into CD8 + CD31 - CD45RA - memory (CD31 - memory) Tregs/Tresps and its effect on the release of cytokines, Fas receptor, Fas ligand as well as cytotoxic mediators by naïve, central memory (CM), effector memory (EM), and terminally differentiated effector memory (TEMRA) Tresps. We found that normal age-dependent differentiation of CD8 + Tregs/Tresps generally differs in the way that TEMRA cells only arise in Tresps. Compared to healthy controls, KF patients revealed an age-independently decreased frequency of CCR7 + RTE Tregs/Tresps, but increased frequencies of CCR7 + MN Tregs/Tresps and CD31 - memory Tregs/Tresps, suggesting an increased differentiation via CD31 + CD45RA - memory (CD31 + memory) Tregs/Tresps into CD31 - memory Tregs/Tresps. Intensified differentiation via CD31 + memory Tresps increased the emergence of apoptosis-resistant CM Tresps with strong Fas ligand-mediated cytotoxicity. CCR7 + RTE Tresp proliferation generated TEMRA Tresps, secreting high levels of cytotoxic mediators. In dialysis and transplant patients, CD31 + TEMRA Tregs/Tresps accumulated, proposing an impaired CCR7 + RTE Treg/Tresp differentiation via CD31 + memory Tregs/Tresps into CD31 - memory Tregs/Tresps. Increased percentages of CD31 - TEMRA Tresps, but not of CD31 - TEMRA Tregs, were observed in all patient groups, indicating impaired proliferation of CCR7 + RTE Tresps, but not of CCR7 + RTE Tregs, into CD31 - memory Tregs/Tresps. In transplant patients, CCR7 + RTE Tregs accumulated, while frequencies of CCR7 + RTE Tresps were decreased, suggesting that the immunosuppressive therapy only prevented excessive CCR7 + RTE Treg differentiation but not that of CCR7 + RTE Tresps. Presumably, this caused the accumulation of TEMRA Tresps with decreased release of cytotoxic mediators, such as perforin. In conclusion, we propose that chronic KF affects both the differentiation of CD8 + Tregs and CD8 + Tresps. However, the immunosuppressive therapy after transplantation may successfully prevent excessive Treg differentiation, but not as suffciently that of Tresps. Therefore, the risk for graft rejection may be reduced, while the susceptibility for infections and malignancies may be increased in these patients.

Human ageing is accompanied by poor responses to infection and decreased vaccine efficacy. While the causes of this can be attributed to defects in the immune system that increase with age, it is unknown whether mitochondrial dysfunction may also contribute to these phenomena. This study aims to assess mitochondrial dysfunction in CD4+ terminal effector memory T cells re-expressing CD45RA (TEMRA) cells and other CD4+ memory T cell subtypes, which are increased in number in the elderly population, with respect to how their metabolic responses to stimulation are altered compared to CD4+ naïve T cells. In this study, we show that CD4+ TEMRA cells exhibit altered mitochondrial dynamics compared to CD4+ naïve cells and CD4+ central and effector memory cells, with a 25% reduction in OPA1 expression. CD4+ TEMRA and memory cells show increased upregulation of Glucose transporter 1 following stimulation and higher levels of mitochondrial mass compared to CD4+ naïve T cells. Additionally, TEMRA cells exhibit a decrease in mitochondrial membrane potential compared to other CD4+ memory cell subsets by up to 50%. By comparing young to aged individuals, more significant mitochondria mass and lower membrane potential were observed in CD4+ TEMRA of young individuals. In conclusion, we suggest that CD4+ TEMRA cells may be impaired with respect to their metabolic response to stimulation, possibly contributing to impaired responses to infection and vaccination.

Aim: This study aimed to characterize and compare the composition of central (TCM), effector (TEM), tissue-resident (TRM), and terminally differentiated (TEMRA) memory T cells in mid-luteal endometrium during the window of implantation (WOI) in women with and without a previous miscarriage. Methods: Stromal lymphocytes from endometrial samples (P + 5) were analyzed by multicolor flow cytometry to quantify total, CD4+ and CD8+ TCM (CD45RA−CCR7+), TEM (CD45RA−CCR7−), TRM (CD69+), and TEMRA (CD45RA+CCR7−) subsets. Participants were grouped as having no previous miscarriage (n = 38) or ≥1 previous miscarriage (n = 33), and the relative distribution of these memory subsets was compared between groups. Correlations, PCA and logistic regression were used to assess global memory network organization. Results: Women with prior miscarriage exhibited higher TCM proportions among total and CD8+ lymphocytes (p < 0.01), alongside lower CD8+ TEM (p = 0.02) and higher CD4+ TEM (p = 0.01). TRM showed a mild, non-significant increase (p = 0.18), while TEMRA remained stable. TRM correlated positively with both TCM (r = 0.51) and CD4+ TEM (r = 0.40), indicating coordinated organization among memory subsets. Multivariate analyses (PCA and logistic regression) confirmed these trends and identified the TCM/TEM ratio as the most discriminative parameter. Conclusions: Endometrial memory T-cell composition during the WOI differs in women with miscarriage history, characterized by central memory expansion and reduced effector memory proportions, with parallel increases in tissue-resident cells. These changes suggest persistent remodeling of the local immune memory network toward a long-lived, less differentiated phenotype that may influence implantation readiness in subsequent cycles.

Radiotherapy (RT) of the brain is a common treatment for patients with high-grade gliomas and brain metastases. It has previously been shown that reactivation of cytomegalovirus (CMV) frequently occurs during RT of the brain. This causes neurological decline, demands antiviral treatment, and is associated with a worse prognosis. CMV-specific T cells are characterized by a differentiated effector memory phenotype and CD45RA+ CCR7- effector memory T (TEMRA) cells were shown to be enriched in CMV seropositive individuals. In this study, we investigated the distribution of TEMRA cells and their subsets in the peripheral blood of healthy donors and, for the first time, prospectively within the scope of the prospective Glio-CMV-01 clinical trial of patients with high-grade glioma and brain metastases during radiation therapy as a potential predictive marker. First, we developed a multicolor flow cytometry-based assay to monitor the frequency and distribution of TEMRA cells in a longitudinal manner. The CMV serostatus and age were considered as influencing factors. We revealed that patients who had a reactivation of CMV have significantly higher amounts of CD8+ TEMRA cells. Further, the distribution of the subsets of TEMRA cells based on the expression of CD27, CD28, and CD57 is highly dependent on the CMV serostatus. We conclude that the percentage of CD8+ TEMRA cells out of all CD8+ T cells has the potential to serve as a biomarker for predicting the risk of CMV reactivation during RT of the brain. Furthermore, this study highlights the importance of taking the CMV serostatus into account when analyzing TEMRA cells and their subsets.

Aims The BioBone consortium aims to validate circulating CD8 + TEMRA cells as a prognostic biomarker for predicting impaired fracture healing outcomes in a prospective, blinded, multicenter clinical study. The primary performance parameters are the pre-operative identification of at least 30% of patients who ultimately experience impaired healing at the first clinical endpoint, with a specificity greater than 90% to minimize the false-positive rate. Methods BioBone is a prospective, blinded, multicenter biomarker validation study designed to assess the prognostic value of circulating CD8 + TEMRA cells in fracture healing. A total of 640 patients aged 18 to 80 years with fractures of the humeral diaphysis, radial and/or ulnar diaphysis, femoral neck, trochanteric femur, femoral diaphysis, distal femur, proximal tibia, tibial diaphysis and distal tibia will be enrolled. The study is powered to validate the target assay performance and accounting for 6–7 potential confounders at an expected incidence of 10% impaired healing. Biomarker levels will be measured pre- and post-operatively using flow cytometry (FC) and patients will be monitored for one year. The primary endpoint is fracture healing status at 17–19 weeks (normal healing or delayed healing), while the secondary endpoint evaluates healing at nine months (delayed healing or pseudarthrosis). Fracture consolidation will be assessed through radiographs or computed tomography (CT) scans in conjunction with clinical assessments such as range of motion and weight-bearing capacity. Key outcome measures include radiographic analysis (RUST/RUSH scores), functional and patient-reported outcomes (e.g. weight bearing ability, range of motion, and the SF-36 questionnaire), as well as socioeconomic parameters (e.g. work capacity, rehabilitation needs, mobility). The predictive performance (sensitivity, specificity, NPV, PPV) of the biomarker will be determined in a prospective, double-blinded analysis, where CD8 + TEMRA blood levels are measured prior to surgical treatment and healing status at clinical endpoints is assessed by independent observers. Additional immunological examination and in vitro analysis of blood and fracture hematoma samples will further investigate the mechanism of action of CD8 + TEMRA cells in impaired human bone regeneration. Conclusion The BioBone study will validate the suitability of CD8 + TEMRA cells as a prognostic marker for impaired fracture healing and their integration into routine clinical practice. The results could have a global impact by incorporating immune-based prognostic tools into clinical workflows, paving the way for precision medicine approaches in trauma care. The BioBone study is funded by the German Federal Ministry of Education and Research (BMBF).