Search Results (97)

T lymphocytes infiltrate the CNS in response to murine cytomegalovirus (MCMV) infection and form a pool of long-lived brain tissue-resident memory T-cells (bT_RMs), which display markers of residency (i.e., CD103, CD69, CD49a). However, the functional role of these bT_RMs is still unknown. By 30 days postinfection, a latent viral brain infection was established, as indicated by absence of viral transcripts (IE1, E1, and gB) produced during productive infection. Following intracerebroventricular injection of either depleting α-CD8 Ab (clone YTS169.4) or α-CD103-sap (clone IT50) into the brain, 90–95% T-cell depletion was achieved. Using luciferase-expressing mice, we observed recommenced imaging signals indicative of de novo MCMV IE promoter activity in depleted animals. Surprisingly, using an explant assay, we efficiently recovered reactivatable, infectious virus from untreated, latent animals, but not from those depleted of bT_RMs (viral recovery in explants was reduced from 100% to 50% by day 21). We identified Lgals3 (galectin 3), Gpnmb (glycoprotein nonmetastatic melanoma protein B) and Hmox1 (heme oxygenase 1) as genes that were most upregulated in bT_RM-depleted groups. When bT_RMs were depleted, there was transient expression of viral IE genes which resulted in antiviral microglia with a phagocytic, disease-associated (DAM) or neurodegenerative (MGnD) phenotype. These data provide new insights into the role of bT_RMs in controlling both CNS reactivation and driving microglial phenotypes. Full article

Ribose 2′-O-methylation (Nm), a key RNA modification, is catalyzed by diverse 2′-O-methyltransferases (2′-O-MTases), yet the evolutionary trajectories of these enzymes remain poorly studied. Here, with a comprehensive collection of functionally validated 2′-O-MTases, we classified them into 11 families based on the distinct methyltransferase (MTase) domains. Homology searches across 198 species identified 6746 proteins, revealing the widespread distribution of 2′-O-MTases across the Tree of Life. Eight MTase domains (e.g., FtsJ, SpoU-methylase) existed both in eukaryotes and prokaryotes, indicating their ancient origin in the Last Universal Common Ancestor (LUCA). In contrast, the AdoMet-MTase, TRM13, and Trm56 domains are lineage-specific. Copy number expansion of most 2′-O-MTase families occurred as life evolved from prokaryotes to eukaryotes, where they might engage in more complex regulation of cell differentiation and development. Domain composition, Ka/Ks ratio, and domain structural analyses showed that purifying selection conserved catalytic domains across most families, despite the frequent integration of auxiliary domains. Notably, the FtsJ family diverged into three deeply separated lineages via remodeling the catalytic pocket, with each lineage specializing in the methylation of mRNA caps, rRNA, or tRNA. These findings illuminate the evolutionary trajectory of 2′-O-MTases, highlighting their ancient multiple origins and functional diversification. Full article

Background: GATA2-related myelodysplastic syndrome (GATA2-MDS) is a unique predisposition syndrome with a high risk of leukemic transformation. This systematic review synthesizes current literature and presents two illustrative pediatric GATA2-MDS cases. Methods: Data retrieval from eight cohort and case–control studies provides comprehensive analysis on disease features, diagnostic complexities, management, and outcomes related to hematopoietic stem cell transplantation (HSCT) in GATA2-related myeloid malignancies. Additionally, two pediatric cases are included to exemplify clinical and therapeutic challenges in real-world setting. Results: The literature data demonstrates high incidence of monosomy 7, and recurrent infections as the most common clinical feature, followed by immunodeficiency and lymphedema. Prognosis clearly worsens with age and HSCT remains the only curative treatment. GATA2 patients undergoing HSCT experience high rates of graft versus host disease (GvHD) as well as unique neurological, thrombotic, and infectious complications. Transplant-related mortality (TRM) is linked to GvHD and infections. Post-transplant cyclophosphamide (PT/Cy) strategies seem to improve survival by reducing GvHD incidence. Overall survival (OS) remains variable across groups. The first case presents rapid disease progression to pulmonary alveolar proteinosis (PAP) and leukemic transformation, further developing severe HSCT complications. The second case addresses novel GATA2 mutation and raises concerns regarding alternative prophylactic and therapeutic strategies in transplant setting. Conclusions: Collaborative efforts aim to enhance understandings of GATA2-related myeloid malignancies and guide towards more effective management approaches. Full article

Background: Cytomegalovirus (CMV) infection and age impact immune responses to vaccines. The effect of sex remains controversial. We investigated the relationship between cytomegalovirus-seropositivity, age, and sex and the immunogenicity of the recombinant (RZV) and live (ZVL) zoster vaccines in adults ≥50 years of age. Methods: Varicella zoster virus (VZV) glycoprotein E (gE)-specific antibody, antibody avidity, and cell-mediated immunity (CMI) were measured pre-vaccination and at regular intervals over 5 years post-vaccination in 80 RZV and 79 ZVL recipients, including 91 cytomegalovirus-seropositive and 90 female participants. Results: Differences associated with CMV-seropositivity: lower VZV-gE-CMI in RZV recipients after the first dose of vaccine, but no differences after the 2nd dose; lower VZV-gE-specific antibody avidity in ZVL recipients; and more abundant Th1 and senescent T cells (Tsen) and less abundant regulatory (Treg) and tissue-resident memory T cells (Trm). Differences associated with older age: lower antibody responses in RZV recipients and lower Th1 cells. Differences associated with sex: none for immunogenicity of either vaccine. Differences associated with T cell subset abundance: higher Tsens and lower Tregs or Trms were associated with lower post-dose 1 VZV-gE-specific CMI in RZV recipients, and higher Th1s were associated with higher antibody concentrations. Conclusions: The correlation of CMV- and age-associated T cell subsets with the immunogenicity of ZVLs and RZVs suggests that T cell imprinting contributes to the effect of age and CMV on vaccine responses. Full article

We previously described that elevated levels of the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) during the early phase of allogeneic hematopoietic stem-cell transplantation (HSCT) can predict one-year transplant-related mortality (1y-TRM). Given that the liver and kidneys are the primary organs responsible for the effective conversion of vitamin D3, we investigated whether liver and/or kidney function, inflammation, or patient sex might influence vitamin D3 metabolism and, consequently, patient outcomes during transplantation. We found that female patients exhibited higher levels of 1,25(OH)2D3 at the time of transplantation compared with male patients. However, 1,25(OH)2D3 levels were associated with 1y-TRM in both sexes. No correlation was found between liver-associated markers, such as bilirubin, or the inflammation marker C-reactive protein (CRP) and serum levels of vitamin D3 metabolites in either female or male patients. However, serum levels of 1,25(OH)2D3, but not 25(OH)D3 correlated with the creatinine-based estimated glomerular filtration rate (eGFR), indicating that 1,25(OH)2D3 levels are associated with kidney function in HSCT patients. However, a Cox regression analysis, adjusted for baseline risk factors, demonstrated that high peri-transplant levels of 1,25(OH)2D3 (measured from days −2 to 7) remained a significant predictor of patient survival, even when eGFR was taken into account (hazard ratio = 0.99; p = 0.004). These findings suggest that optimal serum levels of 1,25(OH)2D3 may not be achievable in some HSCT patients and that kidney function alone cannot explain why some patients fail to reach the optimal 1,25(OH)2D3 threshold. These data support the potential use of 1,25(OH)2D3 as a prophylactic agent, particularly in patients with pre-existing kidney disease. Full article

The treatment of B-cell acute lymphoblastic leukemia (B-ALL) in adults remains a significant therapeutic challenge. While advances in chemotherapy and targeted and immunotherapies have improved overall survival, relapsed or refractory (r/r) adult ALL is associated with poor outcomes. CD19-directed chimeric antigen receptor (CAR) T-cell therapy has emerged as a transformative option, achieving high remission rates even in heavily pretreated patients. However, relapse is common. Allogeneic hematopoietic stem cell transplantation (allo-HCT), a traditional cornerstone of remission consolidation, may improve long-term outcomes but carries risks of transplant-related mortality (TRM) and morbidity. Most evidence for HCT after CAR T therapy comes from retrospective analyses of subgroups from CAR T cell trials, with small sample sizes and inconsistent data on transplant procedures and outcomes. Despite these limitations, consolidative allo-HCT appears to prolong relapse-free survival (RFS). While overall survival (OS) benefits are in question, extended remission duration has been observed. Nonrelapse mortality (including TRM), ranging from 2.4 to 35%, underscores the need for careful patient selection. Emerging real-world data affirm these findings but highlight the importance of individualized decisions based on disease and treatment history. This review examines current evidence on the sequential use of CD19-directed CAR T-cell therapy and allo-HCT in adults with r/r B-ALL. Full article

Background: Influenza remains a significant public health challenge, with vaccination being a substantial way to prevent it. Cell-cultured influenza vaccines have emerged to improve on the drawbacks of egg-based vaccines, but there are few studies focusing on T cell immunity with both types of vaccines. Therefore, we studied the following 2022–2023 seasonal influenza vaccines with a standard dose and high dose: cell-based (C_sd and C_hd) and egg-based (E_sd and E_hd) vaccines. Methods: Along with a saline control group, C_sd, C_hd, E_sd, and E_hd vaccines were administered to BALB/c mice, followed by a challenge with the A/Victoria/2570/2019 (H1N1) strain. Results: After the challenge, four out of five mice in the saline group died by day 7 post-infection (P.I.). None of the vaccinated groups experienced over 20% weight loss or any deaths. On day 7 P.I., the lung viral load in the saline group (mean log value of 4.17) was higher than that in the vaccinated groups, with the C_sd group showing the lowest viral load (mean log value of 3.47). The C_sd group showed a significantly high response in macrophage 1 (M1), IFN-γ+ T cells, and tissue-resident memory (T_RM) T cells compared with the E_sd group on day 2 P.I. These M1, IFN-γ+ T cells, and T_RM cells showed similar trends (p < 0.01). In terms of humoral immunity, only the E_hd group showed HAI titers above 40 for all four strains before and after the challenge. Conclusions: The high levels of T cells in the cell-cultured vaccines suggest, pending further real-world research, that these vaccines may offer advantages. Full article

Background: Solid tumors vary by the immunogenic potential of the tumor microenvironment (TME) and the likelihood of response to immunotherapy. The emerging literature has identified key immune cell populations that significantly impact immune activation or suppression within the TME. This study investigated candidate T-cell populations and their differential infiltration within different tumor types as estimated from mRNA co-expression levels of the corresponding cellular markers. Methods: We analyzed the mRNA co-expression levels of cellular biomarkers that define stem-like tumor-infiltrating lymphocytes (TILs), tissue-resident memory T-cells (TRM), early dysfunctional T-cells, late dysfunctional T-cells, activated-potentially anti-tumor (APA) T-cells and Butyrophilin 3A (BTN3A) isoforms, utilizing clinical and transcriptomic data from 1892 patients diagnosed with melanoma, bladder, ovarian, or pancreatic carcinomas. Real-world data were collected under the Total Cancer Care Protocol and the Avatar^® project (NCT03977402) across 18 cancer centers. Furthermore, we compared the survival outcomes following immune checkpoint inhibitors (ICIs) based on immune cell gene expression. Results: In melanoma and bladder cancer, the estimated infiltration of APA T-cells differed significantly (p = 4.67 × 10⁻¹² and p = 5.80 × 10⁻¹², respectively) compared to ovarian and pancreatic cancers. Ovarian cancer had lower TRM T-cell infiltration than melanoma, bladder, and pancreatic (p = 2.23 × 10⁻⁸, 3.86 × 10⁻²⁸, and 7.85 × 10⁻⁹, respectively). Similar trends were noted with stem-like, early, and late dysfunctional T-cells. Melanoma and ovarian expressed BTN3A isoforms more than other malignancies. Higher densities of stem-like TILs; TRM, early and late dysfunctional T-cells; APA T-cells; and BTN3A isoforms were associated with increased survival in melanoma (p = 0.0075, 0.00059, 0.013, 0.005, 0.0016, and 0.041, respectively). The TRM gene signature was a moderate predictor of survival in the melanoma cohort (AUROC = 0.65), with similar findings in testing independent public datasets of ICI-treated patients with melanoma (AUROC 0.61–0.64). Conclusions: Key cellular elements related to immune activation are more heavily infiltrated within ICI-responsive versus non-responsive malignancies, supporting a central role in anti-tumor immunity. In melanoma patients treated with ICIs, higher densities of stem-like TILs, TRM T-cells, early dysfunctional T-cells, late dysfunctional T-cells, APA T-cells, and BTN3A isoforms were associated with improved survival. Full article

Background/Objectives: Respiratory syncytial virus (RSV) causes symptoms similar to a mild cold for adults, but in case of infants, it causes bronchitis and/or pneumonia, and in some cases, mortality. Mucosal immunity within the respiratory tract includes tissue-resident memory T (T_RM) cells and tissue-resident memory B (B_RM) cells, which provides rapid and efficient protection against RSV re-infection. Therefore, vaccine strategies should aim to generate mucosal immune responses. However, the interactions between RSV vaccines and mucosal immune responses within the respiratory tract are poorly understood. We evaluated a mucosal immune system following immunization by RSV vaccine with poly-sorbitol transporter (RSV-PST), a nanoparticle adjuvant. Methods: We intranasally immunized the RSV-PST and identified the systemic and mucosal immune responses. Furthermore, we challenged with RSV A2 strain after immunization and investigated the protective effects. Results: Consequently, antigen-specific CD8⁺ T_RM cells were markedly elevated in the lung parenchyma, yet exhibited impaired cytokine expression. In contrast, humoral immunity, with systemic antibody production from serum, but not in the respiratory tract, was significantly increased by RSV-PST immunization. Interestingly, the production of respiratory mucosal antigen-specific IgG after RSV A2 challenge dramatically increased in the bronchoalveolar lavage fluid (BALF) of the RSV-PST immunized group in the presence of FTY720, and the lung-infected RSV titer was significantly lower in this group. Furthermore, after RSV A2 challenge, CD69⁺ IgG⁺ B_RM cells were significantly increased in lung tissues in the RSV-PST group. Conclusions: The RSV-PST vaccine has protective effects against RSV infection by promoting both systemic and local humoral immunity rather than cellular immunity. Full article

Background/Objectives: Tumor-infiltrating B cells (TIBs) and tissue-resident memory T cells (TRMs) play significant roles in antitumor immunity. However, their prognostic relevance in brain metastases (BMs) derived from gastrointestinal (GI) cancers remains unclear. This study aimed to investigate the prognostic significance of TIBs and TRMs in GI cancer-derived BMs (GIBMs). Methods: Retrospective histopathological analyses were performed on surgically resected GIBM tissues from 13 patients. The densities of tumor-infiltrating lymphocytes (TIL) subsets (TIBs, CD4⁺ T cells, CD8⁺CD103⁺ TRMs, and CD8⁺CD103^- non-TRMs) were quantified and correlated with clinical parameters and overall survival (OS) including the Graded Prognostic Assessment (GPA). Results: TIBs and CD4⁺ T cells were predominantly accumulated in the tumor stroma, particularly around blood vessels, where they formed lymphocyte clusters without characteristics of tertiary lymphoid structures (TLSs). In contrast, TRMs more deeply infiltrated into the tumor epithelium than their counterpart non-TRMs. Positive correlations were found between TIB density and both the prognostic prediction of GPA and overall survival (OS) after BM diagnosis or surgery. Furthermore, increased densities of TIBs and TRMs were associated with enhanced survival after BM diagnosis. Conclusions: TIB and TRM densities in BM tissues could serve as reliable prognostic indicators for survival in patients with GIBMs. This study provides crucial insights for the development of novel immunotherapeutic strategies against this lethal disease. Full article

Retrotransposons are mobile DNA elements that are more active with increasing age and exacerbate aging phenotypes in multiple species. We previously reported an unexpected extension of chronological lifespan in the yeast, Saccharomyces paradoxus, due to the presence of Ty1 retrotransposons when cells were aged under conditions of mild stress. In this study, we tested a subset of genes identified by RNA-seq to be differentially expressed in S. paradoxus strains with a high-copy number of Ty1 retrotransposons compared with a strain with no retrotransposons and additional candidate genes for their contribution to lifespan extension when cells were exposed to a moderate dose of hydroxyurea (HU). Deletion of ADE8, NCS2, or TRM9 prevented lifespan extension, while deletion of CDD1, HAC1, or IRE1 partially prevented lifespan extension. Genes overexpressed in high-copy Ty1 strains did not typically have Ty1 insertions in their promoter regions. We found that silencing genomic copies of Ty1 prevented lifespan extension, while expression of Ty1 from a high-copy plasmid extended lifespan in medium with HU or synthetic medium. These results indicate that cells adapt to expression of retrotransposons by changing gene expression in a manner that can better prepare them to remain healthy under mild stress. Full article

The development of a tuberculosis (TB) vaccine is imperative. Employing multi-stage Mycobacterium tuberculosis (Mtb) antigens as targeted antigens represents a critical strategy in establishing an effective novel TB vaccine. In this investigation, we evaluated the immunogenicity and protective efficacy of a recombinant adenovirus vaccine expressing two fusion proteins, Ag85B-ESAT6 (AE) and Rv2031c-Rv2626c (R2), derived from multi-stage antigens of Mtb via intranasal administration in mice. Intranasal delivery of Ad-AE-R2 induced both long-lasting mucosal and systemic immunities, with a preferential elicitation of CD8⁺ T cell immunity demonstrated by the accumulation and retention of CD8⁺ T cells in BALF, lung, and spleen, as well as the generation of CD8⁺ TRM cells in BALF and lung tissues. Compared to subcutaneous immunization with Bacillus Calmette-Guerin (BCG), Ad-AE-R2 provided superior protection against high-dose intratracheal BCG challenge, specifically within the lungs of mice. Our findings support the notion that empowering T cells within the respiratory mucosa is crucial for TB vaccine development while highlighting targeting CD8⁺ T cell immunity as an effective strategy for optimizing TB vaccines and emphasizing that eliciting systemic memory immunity is also vital for the successful development of a TB mucosal vaccine. Furthermore, our results demonstrate that the BCG challenge serves as a convenient and efficient method to evaluate candidate vaccine efficacy. Full article

From established latency, human herpes virus type 2 (HSV-2) frequently reactivates into the genital tract, resulting in symptomatic ulcers or subclinical shedding. Tissue-resident memory (T_RM) CD8+ T cells that accumulate and persist in the genital skin at the local site of recrudescence are the “first responders” to viral reactivation, performing immunosurveillance and containment and aborting the ability of the virus to induce clinical lesions. This review describes the unique spatiotemporal characteristics, transcriptional signatures, and noncatalytic effector functions of T_RM CD8+ T cells in the tissue context of human HSV-2 infection. We highlight recent insights into the intricate overlaps between intrinsic resistance, innate defense, and adaptive immunity in the tissue microenvironment and discuss how rapid virus–host dynamics at the skin and mucosal level influence clinical outcomes of genital herpes diseases. Full article

Gastrointestinal cancers, which include a variety of esophageal and colorectal malignancies, present a global health challenge and require effective treatment strategies. In the evolving field of cancer immunotherapy, tissue-resident memory T cells (Trm cells) have emerged as important players in the immune response within nonlymphoid tissues. In this review, we summarize the characteristics and functions of Trm cells and discuss their profound implications for patient outcomes in gastrointestinal cancers. Positioned strategically in peripheral tissues, Trm cells have functions beyond immune surveillance, affecting tumor progression, prognosis, and response to immunotherapy. Studies indicate that Trm cells are prognostic markers and correlate positively with enhanced survival. Their presence in the tumor microenvironment has sparked interest in their therapeutic potential, particularly with respect to immune checkpoint inhibitors, which may improve cancer treatment. Understanding how Trm cells work will not only help to prevent cancer spread through effective treatment but will also contribute to disease prevention at early stages as well as vaccine development. The role of Trm cells goes beyond just cancer, and they have potential applications in infectious and autoimmune diseases. This review provides a thorough analysis of Trm cells in gastrointestinal cancers, which may lead to personalized and effective cancer therapies. Full article

Allogeneic hematopoietic stem cell transplantation has become a treatment option for otherwise non-curative conditions, both malignant and benign, affecting children and adults. Nevertheless, the latest research has been focusing extensively on transplantation from related and unrelated haploidentical donors, suitable for patients requiring emergent hematopoietic stem cell transplantation (HSCT) in the absence of an HLA-matched donor. Haploidentical HSCT (haplo-HSCT) can be an effective treatment for non-malignant pediatric disorders, such as primary immunodeficiencies or hemoglobinopathies, by enabling a much quicker selection of the appropriate donor for virtually all patients, low incidence of graft-versus-host disease (GVHD), and transplant-related mortality (TRM). Moreover, the outcomes of haplo-HSCT among children with hematological malignancies have improved radically. The most demanding tasks for clinicians are minimizing T-cell-mediated alloreactivity as well as early GVHD prevention. As a result, several T-cell depletion approaches, such as ex vivo T-cell depletion (TCD), and T-cell replete approaches, such as a combination of anti-thymocyte globulin (ATG), post-transplantation cyclophosphamide (PTCy), cyclosporine/tacrolimus, mycophenolate mofetil, or methotrexate, have been taken up. As more research is needed to establish the most beneficial form of therapy, haplo-HSCT is currently considered an alternative donor strategy for pediatric and adult patients with complications like viral and bacterial infections, invasive fungal disease, and GVHD. Full article