• IMMUNE NETWORK
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• v.23 no.4
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• pp.32.1-32.15
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• 2023

Most influenza vaccines currently in use target the highly variable hemagglutinin protein to induce neutralizing antibodies and therefore require yearly reformulation. T cell-based universal influenza vaccines focus on eliciting broadly cross-reactive T-cell responses, especially the tissue-resident memory T cell (T_RM) population in the respiratory tract, providing superior protection to circulating memory T cells. This study demonstrated that intramuscular (i.m.) administration of the adenovirus-based vaccine expressing influenza virus nucleoprotein (rAd/NP) elicited weak CD8 T_RM responses in the lungs and airways, and yielded poor protection against lethal influenza virus challenge. However, a novel "prime-and-deploy" strategy that combines i.m. vaccination of rAd/NP with subsequent intranasal administration of an empty adenovector induced strong NP-specific CD8⁺ T_RM cells and provided complete protection against influenza virus challenge. Overall, our results demonstrate that this "prime-and-deploy" vaccination strategy is potentially applicable to the development of universal influenza vaccines.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.24 no.4
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• pp.377-383
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• 2021

Purpose: We investigated the association of effector memory (EM) CD8⁺ T cell and CD4⁺ T cell immunity with metabolic syndrome (MS). Methods: Surface and intracellular staining of peripheral blood mononuclear cells was performed. Anti-interleukin-7 receptor-alpha (IL-7Rα) and CX3CR1 antibodies were used to stain the subsets of EM CD8⁺ T cells, while anti-interferon-gamma (IFN-γ), interleukin-17 (IL-17), and forkhead box P3 (FOXP3) antibodies were used for CD4⁺ T cell subsets. Results: Of the 47 obese children, 11 were female. Children with MS had significantly higher levels of serum insulin (34.8±13.8 vs. 16.4±6.3 µU/mL, p<0.001) and homeostasis model assessment of insulin resistance (8.9±4.1 vs. 3.9±1.5, p<0.001) than children without MS. Children with MS revealed significantly higher frequencies of IL-7Rα^low CD8⁺ T cells (60.1±19.1% vs. 48.4±11.5%, p=0.047) and IL-7Rα^lowCX3CR1⁺ CD8⁺ T cells (53.8±20.1% vs. 41.5±11.9%, p=0.036) than children without MS. As the serum triglyceride levels increased, the frequency of IL-7Rα^lowCX3CR1⁺ and IL-7Rα^highCX3CR1^- CD8⁺ T cells increased and decreased, respectively (r=0.335, p=0.014 and r=-0.350, p=0.010, respectively), in 47 children. However, no CD4⁺ T cell subset parameters were significantly different between children with and without MS. Conclusion: In obese children with MS, the changes in immunity due to changes in EM CD8⁺ T cells might be related to the morbidity of obesity.

• IMMUNE NETWORK
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• v.11 no.5
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• pp.299-306
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• 2011

Background: $CD4^+Fop3^+$ regulatory T cells (Tregs) are needed to maintain peripheral tolerance, but their role in the development of autoimmune arthritis is still debated. The present study was undertaken to investigate the mechanism by which Tregs influence autoimmune arthritis, using a mouse model entitled K/BxN. Methods: We generated Treg-deficient K/BxNsf mice by congenically crossing K/BxN mice with Foxp3 mutant scurfy mice. The arthritic symptoms of the mice were clinically and histopathologically examined. The proportions and activation of $CD4^+$ T cells and/or dendritic cells were assessed in the spleens, draining lymph nodes and synovial tissue of these mice. Results: K/BxNsf mice exhibited earlier onset and more aggressive progression of arthritis than their K/BxN littermates. In particular, bone destruction associated with the influx of numerous RANKL+ cells into synovia was very prominent. They also contained more memory phenotype $CD4^+$ T cells, more Th1 and Th2 cells, and fewer Th17 cells than their control counterparts. Plasmacytoid dendritic cells expressing high levels of CD86 and CD40 were elevated in the K/BxNsf synovia. Conclusion: We conclude that Tregs oppose the progression of arthritis by inhibiting the development of $RANKL^+$ cells, homeostatically proliferating $CD4^+$ T cells, Th1, Th2 and mature plasmacytoid dendritic cells, and by inhibiting their influx into joints.

• IMMUNE NETWORK
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• v.23 no.4
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• pp.35.1-35.16
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• 2023

Defining the molecular dynamics associated with T cell differentiation enhances our understanding of T cell biology and opens up new possibilities for clinical implications. In this study, we investigated the dynamics of CD5 expression in CD8⁺ T cell differentiation and explored its potential clinical uses. Using PBMCs from 29 healthy donors, we observed a stepwise decrease in CD5 expression as CD8⁺ T cells progressed through the differentiation stages. Interestingly, we found that CD5 expression was initially upregulated in response to T cell receptor stimulation, but diminished as the cells underwent proliferation, potentially explaining the differentiation-associated CD5 downregulation. Based on the proliferation-dependent downregulation of CD5, we hypothesized that relative CD5 expression could serve as a marker to distinguish the heterogeneous CD8⁺ T cell population based on their proliferation history. In support of this, we demonstrated that effector memory CD8⁺ T cells with higher CD5 expression exhibited phenotypic and functional characteristics resembling less differentiated cells compared to those with lower CD5 expression. Furthermore, in the retrospective analysis of PBMCs from 30 non-small cell lung cancer patients, we found that patients with higher CD5 expression in effector memory T cells displayed CD8⁺ T cells with a phenotype closer to the less differentiated cells, leading to favorable clinical outcomes in response to immune checkpoint inhibitor (ICI) therapy. These findings highlight the dynamics of CD5 expression as an indicator of CD8⁺ T cell differentiation status, and have implications for the development of predictive biomarker for ICI therapy.

• Molecules and Cells
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• v.39 no.8
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• pp.603-610
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• 2016

Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic.

• IMMUNE NETWORK
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• v.4 no.3
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• pp.143-154
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• 2004

Background: CD27 is recently known as a memory B cell marker and is mainly expressed in activated T cells, some B cell population and NK cells. CD27 is a member of tumor necrosis factor receptor family. Like CD40 molecule, CD27 has (P/S/T/A) X(Q/E)E motif for interacting with TNF receptor-associated factors (TRAFs), and TRAF2 and TRAF5 bindings to CD27 in 293T cells were reported. Methods: To investigate the CD27 signaling effect in B cells, human CD40 extracellular domain containing mouse CD27 cytoplamic domain construct (hCD40-mCD27) was transfected into mouse B cell line CH12.LX and M12.4.1. Results: Through the stimulation of hCD40-mCD27 molecule via anti-human CD40 antibody or CD154 ligation, expression of CD11a, CD23, CD54, CD70 and CD80 were increased and secretion of IgM was induced, which were comparable to the effect of CD40 stimulation. TRAF2 and TRAF3 were recruited into lipid-enriched membrane raft and were bound to CD27 in M12.4.1 cells. CD27 stimulation, however, did not increase TRAF2 or TRAF3 degradation. Conclusion: In contrast to CD40 signaling pathway, TRAF2 and TRAF3 degradation was not observed after CD27 stimulation and it might contribute to prolonged B cell activation through CD27 signaling.

• IMMUNE NETWORK
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• v.21 no.2
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• pp.17.1-17.10
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• 2021

Abdominal aortic aneurysm (AAA) is a chronic dilation of the aorta with a tendency to enlarge and eventually rupture, which constitutes a major cause of cardiovascular mortality. Although T-cell infiltrates have been observed in AAA, the cellular, phenotypic, and functional characteristics of these tissue-infiltrating T cells are not fully understood. Here, we investigated the proportional changes of T-cell subsets-including CD4⁺ T cells, CD8⁺ T cells, and γδ T cells-and their effector functions in AAAs. We found that Vδ2⁺ T cells were presented at a higher frequency in aortic aneurysmal tissue compared to normal aortic tissue and PBMCs from patients with AAA. In contrast, no differences were observed in the frequencies of CD4⁺, CD8⁺, and Vδ1⁺ T cells. Moreover, we observed that the Vδ2⁺ T cells from AAA tissue displayed immunophenotypes indicative of CCR5⁺ non-exhausted effector memory cells, with a decreased proportion of CD16⁺ cells. Finally, we found that these Vδ2⁺ T cells were the main source of IL-17A in abdominal aortic aneurysmal tissue. In conclusion, our results suggest that increased Vδ2⁺ T cells that robustly produce IL-17A in aortic aneurysmal tissue may contribute to AAA pathogenesis and progression.

• IMMUNE NETWORK
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• v.20 no.5
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• pp.43.1-43.11
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• 2020

Capicua (CIC) is a transcriptional repressor that regulates several developmental processes. CIC deficiency results in lymphoproliferative autoimmunity accompanied by expansion of CD44^hiCD62L^lo effector/memory and follicular Th cell populations. Deletion of Cic alleles in hematopoietic stem cells (Vav1-Cre-mediated knockout of Cic) causes more severe autoimmunity than that caused by the knockout of Cic in CD4⁺CD8⁺ double positive thymocytes (Cd4-Cre-mediated knockout of Cic). In this study, we compared splenic CD4⁺ T cell activation and proliferation between whole immune cell-specific Cic-null (Cic^f/f;Vav1-Cre) and T cell-specific Cic-null (Cic^f/f;Cd4-Cre) mice. Hyperactivation and hyperproliferation of CD4⁺ T cells were more apparent in Cic^f/f;Vav1-Cre mice than in Cic^f/f;Cd4-Cre mice. Cic^f/f;Vav1-Cre CD4⁺ T cells more rapidly proliferated and secreted larger amounts of IL-2 upon TCR stimulation than did Cic^f/f;Cd4-Cre CD4⁺ T cells, while the TCR stimulation-induced activation of the TCR signaling cascade and calcium flux were comparable between them. Mixed wild-type and Cic^f/f;Vav1-Cre bone marrow chimeras also exhibited more apparent hyperactivation and hyperproliferation of Cic-deficient CD4⁺ T cells than did mixed wild-type and Cic^f/f;Cd4-Cre bone marrow chimeras. Taken together, our data demonstrate that CIC deficiency at the beginning of T cell development endows peripheral CD4⁺ T cells with enhanced T cell activation and proliferative capability.

• Safety and Health at Work
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• v.8 no.2
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• pp.198-205
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• 2017

Background: There are a million ragpickers in India who gather and trade recyclable municipal solid wastes materials for a living. The objective of this study was to examine whether their occupation adversely affects their immunity. Methods: Seventy-four women ragpickers (median age, 30 years) and 65 age-matched control housemaids were enrolled. Flow cytometry was used to measure leukocyte subsets, and leukocyte expressions of $Fc{\gamma}$ receptor I (CD64), $Fc{\gamma}RIII$ (CD16), complement receptor 1 (CD35) and CR3 (CD11b/CD18), and CD14. Serum total immunoglobulin-E was estimated with enzyme-linked immunosorbent assay. Results: Compared with the controls, ragpickers had significantly (p < 0.0001) higher levels of CD8-T-cytotoxic, CD16+CD56+natural killer, and CD4+CD45RO+memory T-cells, but depleted levels of CD19+B-cells. The percentage of CD4+T-helper-cells was lower than the control group (p < 0.0001), but their absolute number was relatively unchanged (p = 0.42) due to 11% higher lymphocyte counts in ragpickers. In ragpickers, the percentages of CD14+CD16+intermediate and CD14dim CD16+nonclassical monocyte subsets were elevated with a decline in CD14+CD16-classical monocytes. The expressions of CD64, CD16, CD35, and CD11b/CD18 on both monocytes and neutrophils, and CD14 on monocytes were significantly higher in ragpickers. In addition, ragpickers had 2.7-times more serum immunoglobulin-E than the controls (p < 0.0001). After controlling potential confounders, the profession of ragpicking was positively associated with the changes. Conclusion: Ragpicking is associated with alterations in both innate (neutrophils, monocytes, and natural killer cell numbers and expression of complement and $Fc{\gamma}$ receptors) and adaptive immunity (numbers of circulating B cells, helper, cytotoxic, and memory T cells).

• Journal of Ginseng Research
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• v.48 no.1
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• pp.68-76
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• 2024

Background: Although the survival outcomes of childhood cancer patients have improved, childhood cancer survivors suffer from various degrees of immune dysfunction or delayed immune reconstitution. This study aimed to investigate the effect of Korean Red Ginseng (KRG) on T cell recovery in childhood cancer patients who underwent autologous hematopoietic stem cell transplantation (ASCT) from the perspective of inflammatory and senescent phenotypes. Methods: This was a single-arm exploratory trial. The KRG group (n = 15) received KRG powder from month 1 to month 12 post-ASCT. We compared the results of the KRG group with those of the control group (n = 23). The proportions of T cell populations, senescent phenotypes, and cytokine production profiles were analyzed at 1, 3, 6, and 12 months post-ASCT using peripheral blood samples. Results: All patients in the KRG group completed the treatment without any safety issues and showed a comparable T cell repopulation pattern to that in the control group. In particular, KRG administration influenced the repopulation of CD4⁺ T cells via T cell expansion and differentiation into effector memory cell re-expressing CD45RA (EMRA) cells. Although the KRG group showed an increase in the number of CD4⁺ EMRA cells, the expression of senescent and exhausted markers in these cells decreased, and the capacity for senescence-related cytokine production in the senescent CD28^- subset was ameliorated. Conclusions: These findings suggest that KRG promotes the repopulation of CD4⁺ EMRA T cells and regulates phenotypical and functional senescent changes after ASCT in pediatric patients with cancer.