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Humoral and cellular immune responses to CoronaVac up to one year after vaccination.

Coronavac is a widely used SARS-CoV-2 inactivated vaccine, but its long-term immune response assessment is still lacking. We evaluated SARS-CoV-2-specific immune responses, including T cell activation markers, antigen-specific cytokine production and antibody response following vaccination in 53 adult and elderly individuals participating in a phase 3 clinical trial. Activated follicular helper T (Tfh), non-Tfh and memory CD4+ T cells were detected in almost all subjects early after the first vaccine dose. Activated memory CD4+ T cells were predominantly of central and effector memory T cell p

Human papillomavirus 16 (HPV16) and HPV52 E6-specific immunity in HIV-infected adults on combination antiretroviral therapy.

OBJECTIVES: Human papillomavirus (HPV)-associated cancers disproportionately affect those infected with HIV despite effective combination antiretroviral therapy (cART). The primary aim of this study was to quantify HPV16 and HPV52 E6-specific interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) T-cell responses, a correlate of protective immunity, in the first year following cART initiation and subsequently in those patients with suboptimal (sIR) and optimal (oIR) immune reconstitution. METHODS: Ninety-four HIV-infected patients were recruited to the study; a longitudinal cohort of patients

Mechanisms of failure of chimeric antigen receptor T-cell therapy.

PURPOSE OF REVIEW: Although chimeric antigen receptor T (CART)-cell therapy is best recognized for its antitumor effect in relapsed/refractory B-cell hematological cancers, it is still associated with a high relapse rate. RECENT FINDINGS: We firstly analyzed internal immunological and genetic reasons of CD19+ relapse after treatment for R/R B-cell hematological cancers with CART19 cells. The reasons: murine-derived scFv may limit expansion of CART cells. Repeated antigen exposure leads to T-cell exhaustion. Activation of T cells can cause T-cell senescence and high expression of inhibitive re…

SIRT1 is downregulated by autophagy in senescence and ageing.

SIRT1 (Sir2) is an NAD+-dependent deacetylase that plays critical roles in a broad range of biological events, including metabolism, the immune response and ageing1-5. Although there is strong interest in stimulating SIRT1 catalytic activity, the homeostasis of SIRT1 at the protein level is poorly understood. Here we report that macroautophagy (hereafter referred to as autophagy), a catabolic membrane trafficking pathway that degrades cellular components through autophagosomes and lysosomes, mediates the downregulation of mammalian SIRT1 protein during senescence and in vivo ageing. In senesce

CD57 expression correlates with alveolitis severity in subjects with beryllium-induced disease.

BACKGROUND: Despite numerous studies in human beings linking surface phenotype of blood T cells with their functional characteristics, little is known about this relationship on antigen-specific CD4(+) T cells residing in a target organ. OBJECTIVE: The aims of this study were to determine the relationship between CD57 expression, a marker of T-cell senescence, and severity of chronic beryllium disease (CBD) and to determine the phenotypic and functional characteristics that differentiate beryllium-specific CD4(+) T cells in lung and blood. METHODS: CD57 expression on beryllium-responsive IFN…

Mitochondrial DNA Haplogroups, Biomarkers of Inflammation and Immune Activation, and Risk of Diabetes in Veterans With and Without Human Immunodeficiency Virus.

BACKGROUND: Type 2 diabetes mellitus (DM) is common among people with human immunodeficiency virus (HIV). We previously reported that DM risk was greater in women of African ancestry with HIV who had mitochondrial DNA (mtDNA) haplogroup L3. We examined haplogroup associations with DM and selected soluble and cellular immune biomarkers among people with HIV (PWH) and those without HIV in the Veterans Aging Cohort Study (VACS) Biomarker Cohort. METHODS: VACS participants had mtDNA haplogroups determined from genome-wide genotyping and adjudicated DM outcomes. Serum interleukin 6, D-dimer, and s

METTL14 in tumor immunity: epitranscriptomic regulation and therapeutic potential.

N6-methyladenosine (m6A) is the most abundant internal RNA modification, orchestrated by writers, erasers, and readers. METTL14, a key component of the m6A methyltransferase complex, acts as a structural scaffold that ensures substrate recognition and modification precision. Beyond this canonical role, METTL14 regulates multiple biological processes, including chromatin remodeling, transcriptional activity, and senescence-associated signaling. Recent studies highlight its pivotal function in tumor immunity: METTL14 shapes T cell differentiation, CD8+ T cell activation, and the activity of macr

Beyond CAR-T and oncology: broadening chimeric antigen receptor technologies across cell types and diseases.

Chimeric antigen receptor (CAR)-engineered immune cells have revolutionized cancer immunotherapy, expanding from the established success of CAR-T cells to a diverse array of cellular platforms. While seven Food and Drug Administration-approved CAR-T cell products demonstrate unprecedented efficacy in hematologic malignancies, significant limitations persist, including severe inflammatory toxicities, resistance in solid tumors, and manufacturing barriers. These challenges have catalyzed extensive research to extend CAR engineering into alternative effector cell types, such as unconventional T c

The Emerging Role of CD8+ T Cells in Shaping Treatment Outcomes of Patients with MDS and AML.

CD8+ T cells are critical players in anti-tumor immunity against solid tumors, targeted by immunotherapies. Emerging evidence suggests that CD8+ T cells also play a crucial role in anti-tumor responses and determining treatment outcomes in hematologic malignancies like myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). In this review, we focus on the implication of CD8+ T cells in the treatment response of patients with MDS and AML. First, we review reported studies of aberrant functionality and clonality of CD8+ T cells in MDS and AML, often driven by the immunosuppressive bone

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… CD28 Extinction in Human T Cells: Altered Functions and the Program of T-Cell Senescence. Immunol. Rev. 2005;205:158–169. doi: 10.1111/j.0105-2896.2005.00256.x. 133. Ye J., Huang X., Hsueh E.C., Zhang Q., Ma C., Zhang Y., Varvares M.A., Hoft D.F., Peng G. …

CD147 deficiency in T cells prevents thymic involution by inhibiting the EMT process in TECs in the presence of TGFβ.

Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity. Here, we show that the loss of CD147 on T cells prevents thymic senescence, resulting in slowed shrinkage of the thymus with age and increased production of naive T cells. This phenotype is the result of slowing of the epithelial-mesenchymal transition (EMT) process in thymic epithelial cells (TECs), which eventually leads to reduced adipocyte accumulation. In an in vitro coculture system, we found that TGFβ is an important factor in the EMT process in TECs and that it can reduce the expression

Senescence of the immune system in SLE: Pathogenic mechanisms and therapeutic implications.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by loss of immune tolerance and multi-organ inflammation. Although its pathogenesis involves multiple factors, the peak incidence of SLE in individuals over 48 years of age points to immunosenescence as a key driver of the disease.Even in younger patients, SLE frequently often presents as premature aging of the immune system. This review synthesizes recent advances in understanding how immunosenescence drives pathogenesis through immune dysregulation across major lymphocyte and myeloid subsets. Within the ch

Immortalized mesenchymal stromal cells overexpressing alpha-1 antitrypsin protect acinar cells from apoptotic and ferroptotic cell death.

Chronic pancreatitis (CP) is a progressive inflammatory disorder that impairs endocrine and exocrine function. Our previous work showed that mesenchymal stem/stromal cells (MSCs) and MSCs overexpressing alpha-1 antitrypsin (AAT-MSCs) could be therapeutic tools for CP. However, primary MSCs are predisposed to undergo senescence during culture expansion, which limits their therapeutic applications. We generated and characterized immortalized human MSCs (iMSCs) and AAT-MSCs (iAAT-MSCs) and tested their protective effect on 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced acinar cell death in an

Frailty in People with HIV Is Linked to Inflammation, Bone Health, and T-Cell Exhaustion.

BACKGROUND: Little is known about the specific inflammatory networks and immune parameters that drive frailty outcomes in people with HIV (PWH). METHODS: Plasma analytes and T-cell phenotypes from PWH without frailty (0 Fried score, n = 60) and with frailty (≥3 Fried score, n = 60) were measured by Luminex assay or flow cytometry. Multiple least-squares linear regression analysis was used to determine the association of each marker with frailty in unadjusted and adjusted models. Spearman correlations were used to determine the association of plasma analytes with T-cell phenotypes. RESULTS: W

LCMV-mediated loss of virtual memory CD8 T cells yields a functionally enhanced T cell subset.

The unique cytokine responsiveness of virtual memory T (TVM) cells endows them with a potent capacity for bystander activation and effector function. Here, we investigated the antigen-independent impact of microbial infections on TVM cells. While Salmonella typhimurium or influenza A virus had no discernible effect, infection with lymphocytic choriomeningitis virus (LCMV) resulted in a rapid and profound depletion of TVM and true naive (TN) cells. Unlike TN cells, residual TVM cells exhibited a less differentiated phenotype and heightened T cell receptor (TCR) responsiveness, compared to cells

Immune-driven clonal cell selection at the intersection among cancer, infections, autoimmunity and senescence.

Immune surveillance mechanisms play a crucial role in maintaining lifelong immune homeostasis in response to pathologic stimuli and aberrant cell states. However, their persistence, especially in the context of chronic antigenic exposure, can create a fertile ground for immune evasion. These escaping cell phenotypes, harboring a variety of genomic and transcriptomic aberrances, chiefly in human leukocyte antigen (HLA) and antigen presentation machinery genes, may survive and proliferate, featuring a scenario of clonal cell expansion with immune failure characteristics. While well characterized

Growth retardation and leaky SCID phenotype of Ku70-deficient mice.

Ku70, Ku80, and DNA-PKcs are subunits of the DNA-dependent protein kinase (DNA-PK), an enzyme implicated in DNA double-stranded break repair and V(D)J recombination. Our Ku70-deficient mice were about 50% the size of control littermates, and their fibroblasts were ionizing radiation sensitive and displayed premature senescence associated with the accumulation of nondividing cells. Ku70-deficient mice lacked mature B cells or serum immunoglobulin but, unexpectedly, reproducibly developed small populations of thymic and peripheral alpha/beta T lineage cells and had a significant incidence of thy

Immunosenescence is associated with presence of Kaposi's sarcoma in antiretroviral treated HIV infection.

OBJECTIVE: Some antiretroviral treated HIV-infected patients develop Kaposi's sarcoma despite long-term suppression of HIV replication. These Kaposi's sarcoma lesions are consistent with Kaposi's sarcoma observed in the elderly uninfected population ('classical Kaposi's sarcoma'). We investigated potential mechanisms for this phenomenon, focusing on measures of immune activation and T-cell senescence. DESIGN: We compared markers of immunosenescence, naive T cells, activation, and inflammation in CD4+ and CD8+ T cells from antiretroviral-treated participants with new-onset Kaposi's sarcoma (ca…

Essentials of Th17 cell commitment and plasticity.

CD4(+) T helper (Th) cells exist in a variety of epigenetic states that determine their function, phenotype, and capacity for persistence. These polarization states include Th1, Th2, Th17, and Foxp3(+) T regulatory cells, as well as the more recently described T follicular helper, Th9, and Th22 cells. Th17 cells express the master transcriptional regulator retinoic acid-related orphan receptor γ thymus and produce canonical interleukin (IL)-17A and IL-17F cytokines. Th17 cells display a great degree of context-dependent plasticity, as they are capable of acquiring functional characteristics of

Genetic Defects in Phosphoinositide 3-Kinase δ Influence CD8+ T Cell Survival, Differentiation, and Function.

Activated phosphoinositide 3-kinase delta syndrome (APDS), also known as p110 delta-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI), is an autosomal dominant primary human immunodeficiency (PID) caused by heterozygous gain-of-function mutations in PIK3CD, which encodes the p110δ catalytic subunit of PI3K. This recently described PID is characterized by diverse and heterogeneous clinical manifestations that include recurrent respiratory infections, lymphoproliferation, progressive lymphopenia, and defective antibody responses. A major clinical manifes

The PPTC7/BNIP3/NIX axis induces cGAS/STING-mediated senescence and augments CAR-T efficacy by repressing tumor-intrinsic mitophagy.

In multiple myeloma (MM), resistance to B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR-T) treatment continues to limit therapeutic benefit, whereas the tumor-intrinsic factors governing sensitivity to CAR-T remain poorly understood. Here, integrating public single-cell RNA-seq data with transcriptomic profiling of MM cells before and after CAR-T exposure, we identified the mitochondrial protein PPTC7 as a key modulator linking tumor mitophagy to innate immune activation and CAR-T efficacy. Mechanistically, PPTC7 acted as a negative regulator of tumor-intrinsic