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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.

Dengue virus (DENV) is a mosquito-borne flavivirus that causes serious human disease. The current lack of an effective vaccine to simultaneously protect against the four serotypes of DENV in seronegative individuals is a major unmet medical need. Further, the immunological basis for protective immunity in the setting of DENV infection or vaccination is not fully understood. Our team has developed a live attenuated tetravalent dengue virus vaccine that provides complete protection in a human model of dengue virus challenge. The goal of this study was to define, in the context of protective human vaccination, the quality of vaccine-induced DENV-specific CD8+ and CD4+ T cells and the temporal dynamics associated with their formation and maintenance. Multifunctional, DENV-specific CD8+ and CD4+ T cells developed 8–14 days after vaccination and were maintained for at least 6 months. Virus-specific CD8 T+ cells were a mixture of effector memory T cells (TEM) and effector memory T cells re-expressing CD45RA (TEMRA), with TEM cells predominating until day 21 post-vaccination and TEMRA cells thereafter. The majority of virus-specific CD4+ T cells were TEM with a small fraction being TEMRA. The frequency of virus-specific CD8+ and CD4+ T cells were further skewed to the TEMRA phenotype following either a second dose of the tetravalent vaccine or challenge with a single serotype of DENV. Collectively, our study has defined the phenotypic profile of antiviral CD8+ and CD4+ T cells associated with protective immunity to DENV infection and the kinetics of their formation and maintenance.

IntroductionOpen reduction and fixation are the standard of care for treating mandibular fractures and usually lead to successful healing. However, complications such as delayed healing, non-union, and infection can compromise patient outcomes and increase healthcare costs. The initial inflammatory response, particularly the response involving specific CD8+ T cell subpopulations, is thought to play a critical role in healing long bone fractures. In this study, we investigated the role of these immune cell profiles in patients with impaired healing of mandibular fractures.Materials and methodsIn this prospective study, we included patients with mandibular fractures surgically treated at Charité – Universitätsmedizin Berlin, Germany, between September 2020 and December 2022. We used follow-up imaging and clinical assessment to evaluate bone healing. In addition, we analyzed immune cell profiles using flow cytometry and quantified cytokine levels using electrochemiluminescence-based multiplex immunoassays in preoperative blood samples.ResultsOut of the 55 patients enrolled, 38 met the inclusion criteria (30 men and 8 women; mean age 32.18 years). Radiographic evaluation revealed 31 cases of normal healing and 7 cases of incomplete consolidation, including 1 case of non-union. Patients with impaired healing exhibited increased levels of terminally differentiated effector memory CD8+ T cells (TEMRA) and a higher TEMRA to regulatory T cell (Treg) ratio, compared with those with normal healing.ConclusionsOur analysis of mandibular fracture cases confirms our initial hypothesis derived from long bone fracture healing: monitoring the TEMRA to Treg ratio in preoperative blood can be an early indicator of patients at risk of impaired bone healing. Radiologic follow-up enabled us to detect healing complications that might not be detected by clinical assessment only. This study highlights the potential of individual immune profiles to predict successful healing and may form the basis for future strategies to manage healing complications.

Background Immunosenescence, particularly the altered ratio of naïve and memory T cells, contributes to a diminished immune reserve and impaired adaptive immunity in aging and frail populations. The role of TGF-β signaling pathway—a critical hallmark of organismal senescence and T-cell exhaustion—in terminally differentiated effector memory T (Temra) cells remains elusive. We devised single-cell and bulk-cell RNA sequencing (RNA-seq) datasets to identify age-group-specific transcriptional regulatory networks in T cells and elucidate the roles of TGF-β signaling constituents associated with immunosenescence in Temra. Results Analysis of scRNA-seq data from peripheral T cells across healthy human age groups revealed young-specific regulons controlled by FOXP1, TCF7, LEF1, and IKZF1 and old-specific regulons governed by EOMES, TBX21, RUNX3, and NFATC2. Transcription factor (TF)-binding-motif enrichment analysis implicated TGF-β signaling pathway components ZEB2 and TGFBR3 as pivotal target genes coregulated by multiple TFs, potentially facilitating T-cell terminal differentiation and exhaustion. Pseudotime analysis and bulk-cell RNA-seq further corroborated these regulons, validating their association with T-cell self-renewal capacity (young-specific) or effector/terminal differentiation (old-specific). In terms of aging, multiple TGF-β signaling activation components, including TGFB1, TGFBR1, SMAD3, ZEB2, and TGFBR3, were significantly upregulated in CD8 + Temra cells relative to CD8 + naïve T cells. Conclusions Our study used systematic approaches for delineating age-dependent transcriptional networks for T-cell-associated immunosenescence. We identified multiple components of the TGF-β signaling pathway as potential biomarkers of Temra, which are strongly associated with senescence features including impaired differentiation plasticity, high cytotoxicity, and inflammatory chemotaxis capacity.

Keywords: CD8.sup.+ Tregs, T.sub.EMRA cells, Neurodegeneration

Background Age-related immune decline is basically recognized as a key contributor to frailty. However, associations between immune markers, including T cell subsets, and frailty remain inconclusive and data from Southeast Asia are limited. This study investigated CD8⁺ T cell phenotypes and their associations with frailty among community-dwelling older Thai adults, aiming to identify blood-based biomarkers indicative of immune decline related to frailty. Methods In this cross-sectional study, 189 adults aged ≥ 60 years were classified as robust, pre-frail, or frail using Fried’s criteria. CD8⁺ T cell subsets—naïve (TN), central memory, effector memory, and terminally differentiated effector memory RA⁺ (TEMRA)—and expression of CD28 and PD-1 were analyzed by flow cytometry. Multivariable ordinal logistic regression was performed to identify independent predictors of pre-frailty and frailty, with sex-stratified analyses. Results Reduced TN and increased TEMRA CD8⁺ T cells were clearly shown in our study population of older Thai adults. Frail participants exhibited significantly lower TN and higher TEMRA proportions than robust individuals. TN depletion predominated in frail females, whereas TEMRA expansion was more pronounced in frail males. In addition, CD28⁻ and PD-1⁺ phenotypes within the TN gate were increased in frail adults. In the adjusted analyses, the percentage of CD28⁻ TN (OR = 1.649, p  = 0.003), age (OR = 1.222, p  < 0.001), and number of comorbidities (OR = 1.334, p  = 0.003) independently predicted frailty severity. Sex-stratified analyses showed that age and comorbidity burden were consistently associated with frailty, while the association with immune markers was attenuated. Conclusion Alterations in CD8⁺ T cell phenotypes, particularly naïve T cell depletion and increased CD28⁻ cells within the TN subset, were associated with frailty among community-dwelling older Thai adults. Female and male participants exhibited different CD8⁺ T cell subset distributions; however, these sex-specific patterns were not independently associated with frailty. These findings suggest that the immune alterations observed in frailty may partly reflect age-related immune changes and underlying health conditions, while chronological age and multimorbidity remain important factors associated with frailty in this population. Trial registration number Not applicable.

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.

Chronic T cell activation and accelerated immune senescence are hallmarks of HIV infection, which may contribute to the increased risk of cardiometabolic diseases in people living with HIV (PLWH). T lymphocytes play a central role in modulating adipose tissue inflammation and, by extension, adipocyte energy storage and release. Here, we assessed the CD4 and CD8 T cell profiles in the subcutaneous adipose tissue (SAT) and blood of non-diabetic ( = 9; fasting blood glucose [FBG] < 100 mg/dL), pre-diabetic ( = 8; FBG = 100-125 mg/dL) and diabetic ( = 9; FBG ≥ 126 mg/dL) PLWH, in addition to non- and pre-diabetic, HIV-negative controls ( = 8). SAT was collected by liposuction and T cells were extracted by collagenase digestion. The proportion of naïve (T ) CD45RO CCR7 , effector memory (T ) CD45RO CCR7 , central memory (T ) CD45RO CCR7 , and effector memory revertant RA (T ) CD45RO CCR7 CD4 and CD8 T cells were measured by flow cytometry. CD4 and CD8 T and T were significantly enriched in SAT of PLWH compared to blood. The proportions of SAT CD4 and CD8 memory subsets were similar across metabolic status categories in the PLWH, but CD4 T cell expression of the CD69 early-activation and tissue residence marker, particularly on T cells, increased with progressive glucose intolerance. Use of t-distributed Stochastic Neighbor Embedding (t-SNE) identified a separate group of predominantly CD69 T and T cells co-expressing CD57, CX CR1, and GPR56, which were significantly greater in diabetics compared to non-diabetics. Expression of the CX CR1 and GPR56 markers indicate these T and T cells may have anti-viral specificity. Compared to HIV-negative controls, SAT from PLWH had an increased CD8:CD4 ratio, but the distribution of CD4 and CD8 memory subsets was similar irrespective of HIV status. Finally, whole adipose tissue from PLWH had significantly higher expression of TLR2, TLR8, and multiple chemokines potentially relevant to immune cell homing compared to HIV-negative controls with similar glucose tolerance.