• CD4+ T cells
• Th17 cells
• Treg cells
• inflammatory responses
• ischemic stroke
• therapeutic target

• Humans
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/metabolism
• CD4-Positive T-Lymphocytes/drug effects
• Animals
• Ischemic Stroke/immunology
• Ischemic Stroke/therapy
• Ischemic Stroke/metabolism
• Ischemic Stroke/drug therapy

• National Natural Science Foundation of China

• CD26/dipeptidyl peptidase 4
• natural killer T cells

• Humans
• Lupus Erythematosus, Systemic/immunology
• CD8-Positive T-Lymphocytes/immunology
• Adult
• Female
• CD4-Positive T-Lymphocytes/immunology
• Male
• Middle Aged
• Dipeptidyl Peptidase 4/immunology
• Dipeptidyl Peptidase 4/metabolism
• CD28 Antigens/immunology
• CD28 Antigens/metabolism
• Young Adult

• 180101-01 Ministry of Health, Labour, and Welfare, Japan
• 26860760 JSPS KAKENHI
• JSPS Research Fellowships for Young Scientists

• NF-κB pathway
• airway inflammation
• chitooligosaccharides
• house dust mites
• mucus hypersecretion

• Causal relationship 5
• Gout 4
• Immune cells 3
• Inflammatory proteins 2
• Mendelian randomization 1

• Gout/genetics
• Gout/immunology
• Humans
• Mendelian Randomization Analysis
• Genome-Wide Association Study
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/metabolism
• Polymorphism, Single Nucleotide
• Male

• Causal inference
• Diabetic nephropathy
• Immune cells
• Mendelian randomization

• Humans
• Diabetic Nephropathies/genetics
• Diabetic Nephropathies/immunology
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Mendelian Randomization Analysis
• Polymorphism, Single Nucleotide
• White People/genetics
• East Asian People/genetics

• Humans
• Inflammation/immunology
• Aging/immunology
• Aging/physiology
• Gastrointestinal Microbiome
• Immunosenescence
• NF-kappa B/metabolism
• Animals
• Dysbiosis

• cytolytic function
• cytotoxic CD4+CD28− T cells
• inflammation
• interleukin-15-NKG2D
• tissue damage

• Humans
• CD28 Antigens/metabolism
• Interleukin-15
• NK Cell Lectin-Like Receptor Subfamily K/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• CD4-Positive T-Lymphocytes
• Antineoplastic Agents/metabolism
• Lupus Erythematosus, Systemic/metabolism

• 82201996 National Natural Science Foundation of China
• 81971464 National Natural Science Foundation of China
• 2021A1515111072 Guangdong Basic and Applied Basic Research Fund
• JCYJ20220530151811025 Science and innovation commission of shenzhen municipality

• Aging
• CD4(+) T memory cell
• NK cell
• Pregnancy loss
• Terminally differentiated CD4(+) T cell

• Ageing
• CD28- T cells
• EAE susceptibility
• Natural Treg
• Tc17 cell thymic generation
• Thymic atrophy

Kidney transplant (KT) is the most effective treatment for end‐stage renal disease. The immunosuppressant anti‐thymocyte globulin (ATG) has been applied for induction therapy to reduce the risk of acute transplant rejection for patients at high immunological risk. Despite its putative role in replicative stress during immune reconstitution, the effects of ATG on T‐cell immunosenescent changes remain to be understood.

Phenotypic and functional features of senescent T cells were examined by flow cytometry in 116 healthy controls (HC) and 95 KT patients for comparative analysis according to ATG treatment and CMV reactivation. The TCR repertoire was analysed in peripheral blood mononuclear cells (PBMCs) of KT patients.

T cells of KT patients treated with ATG (ATG⁺) show typical immunosenescent features, accumulation of CD28⁻, CD85j⁺ or CD57⁺ T cells, and imbalance of functional T‐cell subsets, compared with untreated KT patients (ATG⁻). Plasma IL‐15 and CMV‐IgG levels were higher in KT patients than in HCs, and the IL‐15 level positively correlated with the frequency of CD28⁻ T cells in KT patients. ATG⁺ patients had a higher prevalence of CMV reactivation, which is associated with an increased frequency of CD28⁻ T cells. As a result, ATG⁺ patients had expanded CMV‐specific T cells and decreased TCR diversity. However, proliferation, cytokine‐producing capacity and polyfunctionality of T cells were preserved in ATG⁺ patients.

Our findings suggest that ATG treatment contributes to the accumulation of senescent T cells, which may have lifelong clinical implications in KT patients. Thus, these patients require long‐term and comprehensive immune monitoring.

• atg
• cd28^‐ t cells
• cmv
• immunosenescence
• kidney transplantation

• CD4 + CD28− T cell
• IL-15
• Lupus
• Lupus nephritis

• CD4CD28null cells
• CD8CD28null cells
• Chronic kidney disease
• Lymphocyte subpopulation
• Panel reactive antibodies

During the current pandemic, the vast majority of COVID-19 patients experienced mild symptoms, but some had a potentially fatal aberrant hyperinflammatory immune reaction characterized by high levels of IL-6 and other cytokines. Modulation of this immune reaction has proven to be the only method of reducing mortality in severe and critical COVID-19. The anti-inflammatory drug baricitinib (Olumiant) has recently been strongly recommended by the WHO for use in COVID-19 patients because it reduces the risk of progressive disease and death. It is a Janus Kinase (JAK) 1/2 inhibitor approved for rheumatoid arthritis which was suggested in early 2020 as a treatment for COVID-19. In this review the AI-assisted identification of baricitinib, its antiviral and anti-inflammatory properties, and efficacy in clinical trials are discussed and compared with those of other immune modulators including glucocorticoids, IL-6 and IL-1 receptor blockers and other JAK inhibitors. Baricitinib inhibits both virus infection and cytokine signalling and is not only important for COVID-19 management but is “non-immunological”, and so should remain effective if new SARS-CoV-2 variants escape immune control. The repurposing of baricitinib is an example of how advanced artificial intelligence (AI) can quickly identify new drug candidates that have clinical benefit in previously unsuspected therapeutic areas.

• COVID-19
• SARS-CoV-2
• anti-cytokine
• antiviral
• baricitinib
• immune modulator

Immunotherapy, an antitumor therapy designed to activate antitumor immune responses to eliminate tumor cells, has been deeply studied and widely applied in recent years. Immune checkpoint inhibitors (ICIs) are capable of preventing the immune responses from being turned off before tumor cells are eliminated. ICIs have been demonstrated to be one of the most effective and promising tumor treatments and significantly improve the survival of patients with multiple tumor types. However, low effective rates and frequent atypical responses observed in clinical practice limit their clinical applications. Hyperprogressive disease (HPD) is an unexpected phenomenon observed in immune checkpoint-based immunotherapy and is a challenge facing clinicians and patients alike. Patients who experience HPD not only cannot benefit from immunotherapy, but also experience rapid tumor progression. However, the mechanisms of HPD remain unclear and controversial. This review summarized current findings from cell experiments, animal studies, retrospective studies, and case reports, focusing on the relationships between various immune cells and HPD and providing important insights for understanding the pathogenesis of HPD.

• hyperprogressive disease
• immune cells
• immune checkpoint inhibitors
• immunotherapy

• Animals
• Humans
• Immune Checkpoint Inhibitors/pharmacology
• Immune Checkpoint Inhibitors/therapeutic use
• Immunologic Factors/therapeutic use
• Immunotherapy
• Neoplasms/pathology
• Retrospective Studies

• Aging
• CNS and lymphoid tissues
• FoxP3+ regulatory T cells
• Multiple sclerosis
• Self-reactive conventional T cells
• Sex difference

• CD4+ T subsets
• interleukin-17 (IL-17)
• member D (NKG2D)
• the elderly
• the natural killer group 2
• traditional Thai massage (TTM)

• meningococcal vaccine
• hiv-1 infection
• bactericidal antibody
• t cell exhaustion
• cxcl-13

• Adolescent
• Antibody Formation
• CD4-Positive T-Lymphocytes
• Child
• HIV Infections
• Humans
• Meningococcal Vaccines

Pro-inflammatory CD4⁺CD28⁻ T cells are characteristic of immunosenescence, but also of several autoimmune/inflammatory diseases. Vasoactive intestinal peptide (VIP) acts as an anti-inflammatory and immunomodulatory mediator on these cells. Our objective was to study the mutual influence between senescent Th cells and VIP axis in early arthritis (EA), comparing with non-EA donors. We characterized the correlation between senescent Th cells and clinic parameters of EA as well as the behavior of senescent Th biomarkers by real-time PCR. Clinical data were systematically recorded at baseline and after 6 months of follow-up. The number of CD4⁺CD28⁻ T cells measured by sorting is higher in patients who initially meet ACR classification criteria for rheumatoid arthritis (RA) compared to those who were classified as undifferentiated arthritis (UA). A slight positive correlation between EA CD4⁺CD28⁻ T cells and CRP or ESR and a negative correlation with bone mineral density were found. Th senescent biomarkers in EA CD4⁺CD28⁻ T cells were similar to donors, however some of them increased after 6 months of follow-up. VPAC receptors were analyzed by real-time PCR and immunofluorescence, and CD4⁺CD28⁻ T cells showed higher expression of VPAC₂ and lower of VPAC₁, VPAC₂ showing a significant increased expression in EA cells. Sorted CD4⁺CD28⁻ T cells were in vitro expanded in presence of VIP, wherein VIP increased senescent biomarker CD27, while it diminished CD57 or NKG2 senescent biomarkers. Our study demonstrates for the first time the existence of a link between senescent Th cells and the VIP axis.

• CD4+CD28− T cells
• VIP
• VPAC receptors
• early arthritis
• rheumatoid arthritis
• senescent Th cells

Paediatric and adolescent patients in need of allogeneic haematopoietic stem cell transplantation (HSCT) generally receive stem cells from older, unrelated or parental donors when a sibling donor is not available. Despite encouraging clinical outcomes, it has been suggested that immune reconstitution accompanied by increased replicative stress and a large difference between donor and recipient age may worsen immunosenescence in paediatric recipients.

In this study, paired samples were collected at the same time from donors and recipients of haploidentical haematopoietic stem cell transplantation (HaploSCT). We then conducted flow cytometry‐based phenotypic and functional analyses and telomere length (TL) measurements of 21 paired T‐cell sets from parental donors and children who received T‐cell‐replete HaploSCT with post‐transplant cyclophosphamide (PTCy).

Senescent T cells, CD28⁻ or CD57⁺ cells, were significantly expanded in patients. Further, not only CD4⁺CD28⁻ T cells, but also CD4⁺CD28⁺ T cells showed reduced cytokine production capacity and impaired polyfunctionality compared with parental donors, whereas their TCR‐mediated proliferation capacity was comparable. Of note, the TL in patient T cells was preserved, or even slightly longer, in senescent T cells compared with donor cells. Regression analysis showed that senescent features of CD4⁺ and CD8⁺ T cells in patients were influenced by donor age and the frequency of CD28⁻ cells, respectively.

Our data suggest that in paediatric HaploSCT, premature immunosenescent changes occur in T cells from parental donors, and therefore, long‐term immune monitoring should be conducted.

• CD28− T cells
• HaploSCT
• immune monitoring
• immunosenescence
• telomere length

Recent animal studies showed T cells have a direct pathogenic role in the development of heart failure (HF). However, which subsets of T cells contribute to human HF pathogenesis and progression remains unclear. We characterized immunologic properties of various subsets of T cells and their clinical implications in human HF. Thirty-eight consecutive patients with newly diagnosed acute HF (21 males, mean age 66 ± 16 years) and 38 healthy control subjects (21 males, mean age 62 ± 12 years) were enrolled. We found that pro-inflammatory mediators, including CRP, IL-6 and IP-10 and the frequencies of CD57⁺ T cells in the CD4⁺ T cell population were significantly elevated in patients with acute HF compared to control subjects. A functional analysis of T cells from patients with acute HF revealed that the CD4⁺CD57⁺ T cell population exhibited a higher frequency of IFN-γ- and TNF-α- producing cells compared to the CD4⁺CD57⁻ T cell population. Furthermore, the frequency of CD4⁺CD57⁺ T cells at baseline and its elevation at the six-month follow-up were significantly related with the development of cardiovascular (CV) events, which were defined as CV mortality, cardiac transplantation, or rehospitalization due to HF exacerbation. In conclusion, CD4⁺CD57⁺ senescent T cells showed more inflammatory features and polyfunctionality and were associated with clinical outcome in patients with acute HF. More detailed study for senescent T cells might offer new opportunities for the prevention and treatment of human HF.

Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28 ^null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28 ^null CD4 T cells.

• CD28 null
• autoimmune disease
• cytomegalovirus infection
• ​​​​​​​CD4 T cell

An accumulating body of evidence suggests that development of autoimmune pathologies leads to thymic dysfunction and changes in peripheral T-cell compartment, which, in turn, perpetuate their pathogenesis. To test this hypothesis, thymocyte differentiation/maturation in rats susceptible (Dark Agouti, DA) and relatively resistant (Albino Oxford, AO) to experimental autoimmune encephalomyelitis (EAE) induction was examined. Irrespective of strain, immunization for EAE (i) increased the circulating levels of IL-6, a cytokine causally linked with thymic atrophy, and (ii) led to thymic atrophy reflecting partly enhanced thymocyte apoptosis associated with downregulated thymic IL-7 expression. Additionally, immunization diminished the expression of Thy-1, a negative regulator of TCRαβ-mediated signaling and activation thresholds, on CD4+CD8+ TCRαβ^lo/hi thymocytes undergoing selection and thereby impaired thymocyte selection/survival. This diminished the generation of mature CD4+ and CD8+ single positive TCRαβ^hi thymocytes and, consequently, CD4+ and CD8+ recent thymic emigrants. In immunized rats, thymic differentiation of natural regulatory CD4+Foxp3+CD25+ T cells (nTregs) was particularly affected reflecting a diminished expression of IL-7, IL-2 and IL-15. The decline in the overall thymic T-cell output and nTreg generation was more pronounced in DA than AO rats. Additionally, differently from immunized AO rats, in DA ones the frequency of CD28- cells secreting cytolytic enzymes within peripheral blood CD4+ T lymphocytes increased, as a consequence of thymic atrophy-related replicative stress (mirrored in CD4+ cell memory pool expansion and p16^INK4a accumulation). The higher circulating level of TNF-α in DA compared with AO rats could also contribute to this difference. Consistently, higher frequency of cytolytic CD4+ granzyme B+ cells (associated with greater tissue damage) was found in spinal cord of immunized DA rats compared with their AO counterparts. In conclusion, the study indicated that strain differences in immunization-induced changes in thymopoiesis and peripheral CD4+CD28- T-cell generation could contribute to rat strain-specific clinical outcomes of immunization for EAE.

• Animals
• Apoptosis/immunology
• Atrophy
• Cell Proliferation
• Encephalomyelitis, Autoimmune, Experimental/immunology
• Encephalomyelitis, Autoimmune, Experimental/pathology
• Female
• Immunization
• Random Allocation
• Rats
• Species Specificity
• Thymocytes/immunology
• Thymocytes/pathology
• Thymus Gland/immunology
• Thymus Gland/pathology

• Ministarstvo Prosvete, Nauke i Tehnološkog Razvoja (RS)