bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mouse tumor vasculature expresses NKG2D ligands and can be targeted by chimeric NKG2D-modified T cells (46.45)
Authors: Zhang Tong , Sentman Charles 
Published: January 2023

Abstract
Tumor angiogenesis plays an important role in the development and progression of solid tumors. Targeting the tumor vasculature has emerged as a strategy to prevent growth and progression of solid tumors. In this study, we showed that murine tumor vasculature express Rae1, a ligand for a stimulatory natural killer receptor NKG2D. By genetic modification of T cells with a chimeric NKG2D receptor (chNKG2D), in which the NKG2D receptor is fused to the signaling domain of CD3ζ chain, we generated T cells that are capable of targeting tumor vasculature, leading to reduced tumor angiogenesis as well as tumor growth in tumors where the tumor cells do not express NKG2D ligands themselves. H5V, an endothelial cell line, expresses Rae1 and can be lysed by chNKG2D-bearing T cells in a perforin-dependent manner. In vitro capillary tube formation by H5V was inhibited by both soluble factors (IFN-γ) and cell-cell contact by chNKG2D T cells. The in vivo anti-tumor angiogenesis efficacy mediated by chNKG2D T cells was also dependent on IFN-γ and perforin. In addition, chNKG2D T cells could inhibit VEGF expression by myeloid derived suppressor cells (MDSCs). In summary, these results provide a novel mechanism for NKG2D-targeting of solid tumors.
ROS-p38 MAPK-Fas/Fas Ligand-Linked Cascade Regulate Bax Translocation and Calcium Redistribution in Salubrinal-Induced Apoptosis of EBV-Transformed B Cells (46.49)
Authors: Park Ga-bin , Kim Yeong Seok , Lee Hyun-Kyung , Song Hyunkeun , Kim Seonghan , Cho Dae-Ho , Lee Wang-Jae , Hur Dae Young 
Published: January 2023

Abstract
The small molecule salubrinal has antiviral activity against herpes simplex virus-1 (HSV-1) and inhibits dephosphorylation of eIF2 alpha. Salubrinal prevents vulnerable cells from going down the cell-death pathway and is deeply associated with ER stress. The Epstein-Barr Virus (EBV), also called human herpesvirus 4 (HHV-4), is a virus of the herpes family (which includes herpes simplex virus) and is one of the most common viruses in humans. However, maintaining hyper-phosphorylated eIF2α state with high doses of salubrinal treatment promotes apoptosis in some cancer cells. In this report, salubrinal inhibited proliferation and induced apoptosis of EBV-transformed B cells in both dose and time dependent manner. Notably, salubrinal induced ROS generation and p38 MAPK activation, which then induced expression of FasL. Moreover, salubrinal subsequently led to activation of caspases, calcium redistribution, Bax translocation, cytochrome c release, and apoptosis. Caspase inhibitors (z-VAD, z-IETD, and z-DEVD), p38 MAPK inhibitor (SB203580) and ROS inhibitor (NAC) recovered salubrinal-induced apoptosis. ZB4, an antagonistic anti-fas Ab, and SB203580 effectively blocked apoptosis without exerting any influence on ROS generation. These findings suggest that salubrinal may be a novel therapeutic approach for EBV-associated malignant diseases.
FoxP3+Tim-3+ Tregs are site-specific suppressors supporting tumor growth by influencing the functional phenotype of tumor-infiltrating lymphocytes (46.5)
Authors: Sakuishi Kaori , Sullivan Jenna , Kuchroo Vijay , Anderson Ana 
Published: January 2023

Abstract
In prior studies, we and others have found Tim-3 to be expressed on exhausted CD8+ tumor infiltrating lymphocytes (TILs). It was shown that anti-Tim-3 antibody treatment together with anti-PD-1/PD-L1 antibody could abrogate tumor growth and effectively restore T cell effector function to exhausted CD8+ T cells (Sakuishi et al 2010, Fourcade et al 2010, Zhou et al 2011, Ngiow et al 2011). Tim-3 is also expressed on CD4+ TILs but its role in tumor immunity has not been addressed. We have found that the majority of FoxP3+ TILs express Tim-3 in multiple tumor models. Kinetic studies in B16F10 melanoma show that the accumulation of FoxP3+Tim3+ cells parallels tumor growth. Interestingly, this accumulation of FoxP3+Tim-3+ cells is not observed in either the tumor draining lymph node or spleen of tumor-bearing mice, indicating site-specific expansion. FoxP3+Tim-3+ cells are higher producers of IL-10 and are more efficient in suppressing FoxP3- effector T cells in vitro when compared to FoxP3+Tim-3- cells. Depleting FoxP3+ regulatory T cells (Tregs) from established B16 melanoma results in tumor regression and modulation of Tim-3 expression on both FoxP3- CD4 and CD8 TILs. Furthermore, Treg depletion influences the development of exhausted phenotype in CD8+ TILs. This is the first report revealing that the Tim-3+ subset of Tregs predominates within tumor and plays an important role in tumor progression in situ by regulating the functional phenotype of FoxP3- CD4+ and CD8+ TILs.
Long-term memory CD4+ T cells - a survival network (47.12)
Authors: Khoruzhenko Stanislav , Jie Chunfa , Sadegh-Nasseri Scheherazade 
Published: January 2023

Abstract
Memory CD4+ T cells specific for a particular antigen can survive for a lifetime of an individual through undefined mechanisms. Previously we have demonstrated that memory CD4+ T cells undergo a state of dormancy during the resolution of infection, and dormant memory T cells survive for the life of mice. To gain an understanding of the genetic programs involved, we examined gene expression profile of memory DO11.10 CD4+ T cells in mice infected with Vaccinia-OVA virus 10.5 months post infection and compared it with gene expression in age-matched old mice. Extensive literature search allowed reverse engineering of genetic network of differentially expressed genes in long-term memory T cells. Pattern of gene expression pointed to the induction of anti-apoptotic and genomic stability pathways. We found that in long term memory CD4+ T cells a shift from glucose to lipid metabolism occurs, along with upregulation of ceramide synthesis and utilization that may favor memory T cell survival. Insulin resistance appears to play a major role in downregulation of glucose metabolism. In conclusion, our data show that in long-term memory CD4+ T cells several major regulatory genes that regulate anti-apoptotic, genomic stability, glucose and lipid metabolism pathways are upregulated and possibly coordinate an overall pro-survival effect.
The tyrosine phosphatase CD45 regulates lymphopenia-induced T cell proliferation (47.15)
Authors: Saunders Amy , Johnson Pauline 
Published: January 2023

Abstract
Lymphopenia-induced T cell proliferation (LIP) occurs naturally in neonates and in patients with depleted T cell numbers due to infection or immunosuppression. LIP occurs in response to an interaction between TCR with self-MHC as well as to cytokines such as IL-7 and IL-15. However, the precise factors that induce and limit LIP are not well understood. CD45 is a leukocyte specific tyrosine phosphatase that reduces the TCR signaling threshold in T cells, modulates TLR signaling in dendritic cells and can negatively regulate cytokine signaling in leukocytes. Given that CD45 deficient mice have severely reduced numbers of T cells in the periphery, we sought to determine whether CD45 might regulate LIP. CD45 deficient mice were crossed with the RAG1 deficient mice to generate CD45RAG deficient mice and LIP was examined in a CD45 sufficient and CD45 deficient environment. LIP was significantly reduced in the spleen and lymph nodes of lymphopenic hosts lacking CD45. This was attributed to a reduced signal to induce T cell proliferation rather than increased cell death or delayed kinetics. Reduced levels of IL-7 but not IL-15 were evident in the spleens of CD45RAG1 deficient mice and CD45 deficient splenic dendritic cells were less efficient at stimulating antigen-induced T cell proliferation. Together this suggests that dendritic cell CD45 is required for optimal LIP and experiments are ongoing to evaluate this possibility.
Regulation of A1 and Mcl-1 from costimulatory signals affects T cell survival (47.2)
Authors: Song Jianxun , Lei Fengyang , Haque Rizwanuel 
Published: January 2023

Abstract
Costimulation is critical for T cell activation. In recent years, advances have been made in studies of costimulation as potential therapies in the treatment of diseases. However, the intracellular signals by which costimulation affects the function of T cells are not fully understood. A1 and Mcl-1, two bcl-2 family proteins are up regulated in effector T cells by ligation with an agonist antibody to the costimulatory molecule OX40 (CD134), which is essential for long-term T cell survival. To determine whether A1 and Mcl-1 are intracellular molecules of OX40, we examined A1 and Mcl-1 expression in primary T cells from wild-type and OX40-deficient mice, and found A1 and Mcl-1 were up-regulated after early T cell activation, but not be maintained in T cells from OX40-deficient mice. In addition, we used retrovirus-mediated transduction to introduce A1 or Mcl-1 into antigen (Ag)-responding T cells from OX40-deficent mice. We found that exogenous expression of A1 or Mcl-1 reversed the survival defect of OX40-deficient T cells both in vitro and in vivo. Moreover, sustained expression of A1 or Mcl-1 in CD8+ T cells from OX40-deficient mice reversed their defect in preventing tumor growth in a murine model. These results indicate that A1 and Mcl-1 are intracellular molecules of OX40, which regulate T cell survival. The data provide new insights into the mechanisms by which costimualtion regulates T cell survival.
Phenotypic and functional immune attributes predicting survival in very elderly people (47.7)
Authors: Pawelec Graham , Maier Andrea , Hähnel Karin , Zelba Henning , de Craen Anton , Roelofs Helene , Slagboom Eline , Westendorp Rudi , Derhovanessian Evelyna 
Published: January 2023

Abstract
The low level of naïve T-cells commonly observed in the elderly is thought to be causally associated with mortality. However this has not been tested in longitudinal studies. Here, we present correlations between peripheral T-cell subsets and 8-year survival in individuals from the population-based prospective Leiden 85-plus Study. Counter-intuitively, a lower frequency of naïve (CD45RA+CCR7+CD27+CD28+) CD8+ T-cells at baseline (&gt;88 years) correlated with significantly better survival, while there was a tendency for the reciprocal accumulation of late-differentiated effector memory cells (CD45RA-CCR7-CD27-CD28-) also to associate with better survival, suggesting that better retention of memory cells specific for previously encountered antigens provided a survival advantage in this particular population. Given the prevalence of Cytomegalovirus (CMV) and its reported association with immunosenescence, we tested whether memory for this potential pathogen was relevant to survival. We found that individuals mounting an exclusively pro-inflammatory ex-vivo response (TNF, IFN-γ, IL-17) to the major CMV target molecules pp65 and IE1 had a significant survival advantage over those also having anti-inflammatory responses (IL-10). These findings suggest that higher levels of naïve T cells are not necessarily associated with a survival advantage and imply that the nature of immunosurveillance against CMV may be crucial for remaining longevity, at least in the very elderly.
Defective CD4 T cell cognate helper functions in response to influenza immunization and infection in aged mice (47.8)
Authors: Lefebvre Julie 
Published: January 2023

Abstract
A poor immune response is a hallmark of aging. Older individuals are more susceptible to infections and respond poorly to new immunization. This is caused, at least in part, by a defective antibody response. We have shown that age-associated defects impair CD4 T cell functions. Since an optimal antibody response requires good CD4 cognate help through T follicular helper (Tfh) cells, we aimed to determine whether the impaired cognate help resulted from defects in the generation and/or functions of Tfh cells in aged mice. The work presented herein shows that the generation of Tfh cells in response to influenza immunization is delayed, reduced and shortened in aged mice compared to young mice. Also fewer Tfh cells are generated in aged mice than in young mice following influenza infection. The Tfh cells generated in aged mice, however, express similar levels of IL-21, BCL-6, CXCR5 and IL-4 mRNA than Tfh cells from young mice. These data suggest that the generation rather than the functions of Tfh cells is impaired in aged mice. The addition of poly(I:C) as an adjuvant to the influenza vaccine increases Tfh generation and antibody production in young and aged mice. We are investigating the mechanisms by which TLR ligands improve the Tfh response.
Human CD1c+ DCs drive the differentiation of CD103+ intraepithelial CD8+ T cells via TGF beta (48.12)
Authors: Yu Chun , Becker Christian , Marches Florentina , Garcia-Sastre Adolfo , Banchereau Jacques , Merad Miriam , Palucka A. Karolina 
Published: January 2023

Abstract
Mucosa is a major site of invasion and replication of pathogens, including influenza virus. However, our understanding of cellular immune responses and their regulation at mucosal sites in the human is limited due to inherent difficulties in assessing cellular interactions using ex vivo systems. Here we analyzed the response of human myeloid dendritic cells (DCs) to live-attenuated influenza virus (LAIV) and the type of CD8+ T cell responses that were generated using human lung tissue samples and humanized mice. Upon LAIV inoculation, the number of CD1c+ (BDCA-1) DCs in the lungs had increased by 16 hours; whereas the number of CD141+ (BDCA-3) remained stable up to three days post inoculation. Both DC subsets acquire flu antigens in vivo and expand specific memory CD8+ T cells ex vivo. However, at an early time point CD141+ DCs are more efficient in expanding CD8+ effector T cells. CD1c+ DCs are able to expand CD8+ T cells at a later time point, and they uniquely expand CD8+ T cells expressing CD103, a receptor for the epithelial cell-specific E-cadherin. CD1c+ DCs induce CD103+CD8+ T cells with the characteristics of cytotoxic intraepithelial T cells owing to the expression of membrane TGF-β. Our results suggest that lung-resident CD141+ DCs launch the effector response early after viral exposure while the role of migratory CD1c+ DCs is to retain the T cells in the epithelium. Thus, myeloid DCs have a major role in the regulation and expansion of memory T cells in mucosa.
p38α signaling programs dendritic cells to drive TH17 cell differentiation and function (48.14)
Authors: Huang Gonghua , Wang Yanyan , Chi Hongbo 
Published: January 2023

Abstract
Dendritic cells (DCs) bridge innate and adaptive immunity, but how DC-derived signals regulate T cell lineage choices and function remains unclear. Our previous study showed that DCs employed the intracellular phosphatase MKP-1 pathway to instruct multiple T cell lineage choices and anti-microbial and inflammatory responses (Huang et al. Immunity 2011). Since MKP-1 is a potent inhibitor of p38α MAP kinase, we investigated the function of p38α in DCs using the CD11c-Cre deletion system. DCs deficient in p38α were unable to drive the differentiation of responding T cells into the TH17 lineage. Mechanistically, p38α controlled IL-6 and IL-27 and further shaped CD86 expression in DCs, thereby establishing a gene-expression program in DCs to direct TH17 development. We further determined the roles of DC-derived p38α in autoimmune, inflammatory and infectious diseases. We found that mice lacking p38α in DCs showed diminished TH17-dependent inflammation in three disease models: experimental autoimmune encephalomyelitis (EAE), colitis and fungal infection. Moreover, inhibition of the p38 activity either by deleting p38α expression or by using the chemical inhibitor markedly ameliorated the disease severity in mice with ongoing EAE, suggesting a key therapeutic effect of p38α in TH17-dependent diseases. In summary, our results identify p38α MAPK signaling as a central pathway in DCs to program TH17 differentiation and inflammation.
CXCR2 and CXCL5 Regulate the IL-17/G-CSF axis and Neutrophil Homeostasis (48.15)
Authors: Mei Junjie , Liu Yuhong , Dai Ning , Hoffmann Christian , Hudock Kristin , Zhang Peggy , Guttentag Susan , Kolls Jay , Oliver Paula , Bushman Frederic , Worthen G. Scott 
Published: January 2023

Abstract
Neutrophil homeostasis is critical for maintaining innate immune surveillance under normal conditions. CXCR2 plays a critical role in neutrophil homeostasis, as Cxcr2-/- mice demonstrate mild neutrophilia and severe neutrophil hyperplasia in the bone marrow. We found that neutrophil CXCR2 inhibits the IL-17A/G-CSF axis that regulates neutrophil homeostasis, while enterocyte-derived CXCL5 in the gut, regulates the IL-17/G-CSF axis and contributes to CXCR2-regulated neutrophil homeostasis. CXCL5-regulated neutrophil homeostasis was completely dependent on G-CSF, and inhibition of IL-17A reduced plasma G-CSF concentrations and marrow neutrophil numbers in both Cxcl5-/- and Cxcr2-/- mice. Cxcr2-/- mice express IL-17A, and show increased IL-17A-producing cells in the lung, terminal ileum and spleen, which include conventional Th17 cells, γδ T cells, and innate immune cells. Most IL-17 producing splenocytes were responsive to IL-1β plus IL-23 in vitro. Depletion of commensal microbes by antibiotic treatment markedly decreased IL-17A and G-CSF expression, neutrophilia and marrow myeloid hyperplasia in Cxcr2-/- mice. These data provide insights regarding the critical role of CXCR2, CXCL5 and commensal bacteria in regulating the IL-17/G-CSF axis and neutrophil homeostasis at mucosal sites, which keeps the set point of innate immunity in tight control.
Inhibition of Indoleamine 2,3-dioxygenase (IDO) enhances the memory CD8 T cell response and modulates the immunodominance hierarchy following influenza infection (48.17)
Authors: Klonowski Kim , Sage Leo , Rose David , Fox Julie , Huang Lei , Barber Jaime , Tompkins S. Mark , Mellor Andrew , Tripp Ralph 
Published: January 2023

Abstract
The generation of heterosubtypic CD8 T cell responses is important for cross-protective immunity against unrelated strains of influenza. The need to maintain tolerance in the lung, however, limits the overall breadth and duration of CD8 T cell responses, warranting a better understanding of mechanisms of immunoregulation at this site. Influenza infection induces pulmonary expression of the tryptophan catabolizing enzyme IDO. Depletion of tryptophan results in suppression of T cell expansion or effector function, T cell anergy, or deletion. We hypothesized that ablation of IDO activity during CD8 T cell priming would enhance the subsequent CD8 T cell memory pool. To test this in vivo, we conditionally ablated IDO activity during the priming phase using the inhibitor 1-methyl tryptophan (1MT). 1MT-treated animals challenged with a lethal dose of a heterosubtypic influenza virus generated a more robust Th1 response, with enhanced migration to the lung airways. Interestingly, the immunodominance hierarchy was also shifted to favor subdominant CD8 T cell epitopes in both 1MT-treated and IDO-deficient animals, likely a result of observed decreased regulatory T cell function. While 1MT treatment did not affect cytotoxicity or viral clearance, pulmonary pathology was reduced in the absence of IDO. Together these data provide evidence that modulation of IDO activity in the context of influenza infection could be exploited in vaccine development to enhance memory CD8 T cell responses.
Ability of LPS to regulate expression of tolerance-related molecules on dendritic cells is blocked by IL-10 deficiency (48.18)
Authors: Zhang Guag-Xian , Zhou Fang , Ciric Bogoljub , Li Hongmei , Yan Yaping , Li Ke , Cullimore Melissa , Lauretti Elisabetta , Dimeco Antonio , Gonnella Patricia , Rostami Abdolmoham 
Published: January 2023

Abstract
Interleukin-10 (IL-10) is an anti-inflammatory cytokine that plays an important role in regulating the local inflammatory immune response, but regulatory mechanisms of this cytokine have not been fully elucidated. Here we demonstrate that IL-10 deficiency renders LPS treatment ineffective in regulating expression of CD40, CD80, CD86, B7-H2 and B7-DC on dendritic cells (DCs) and blocks up-regulation of IL-27. This inability to respond to LPS was found in both IL-10-/- bone marrow-derived and splenic DCs. Compared to wild type DCs, IL-10-/- DCs expressed similar levels of TLR4 and CD14, but produced less LPS binding protein (LBP). The deficiency in LBP production may explain the failure of IL-10-/- DCs to respond normally to LPS. Moreover, lack of IL-10 modulated the proportions of CD11c+CD8+ and CD11c+B220+ DCs, which play an important role in local inflammatory responses and tolerance. IL-10 deficiency also blocked expression of galectin-1, CD205 and CD103, which are necessary for central and peripheral tolerance. While they did not respond to LPS, IL-10-/- DCs produced increased levels of IL-6 and CCL4 after TNF-α treatment. Together, our results demonstrate that IL-10 deficiency affects the immune functions of DCs, which may contribute to the increased severity of autoimmune diseases seen in IL-10-/- mice.
Distinct LLO-specific CD4 T cells infiltrate the intestinal mucosa following oral Listeria monocytogenes infection. (49.16)
Authors: Fu Han-Hsuan , Sheridan Brian , Pham Quynh-Mai , Schubert Wolf-Dieter , Lefrançois Leo 
Published: January 2023

Abstract
We analyzed the mucosal CD4 T cell response to oral Listeria monocytogenes (LM) infection. Early after infection, a subset of blood-borne LLO-specific CD4 T cells expressed α4β7. Subsequently, antigen-specific CD4 T cells accumulated in the lamina propria and intraepithelial lymphocyte compartment where they were retained long-term. These data suggested that priming in the mucosal lymphoid tissues generated mucosa-seeking CD4 T cells with high memory potential. While naïve CD4 T cells contained both Ly6Chigh/CD27high and Ly6Clow/CD27high subsets, most primary and memory mucosal LLO-specific CD4 T cells were Ly6Clow/CD27low. In contrast, LLO-specific CD4 T cells in the spleen and MLN were comprised of four subsets based on CD27 and Ly6C expression. Upon challenge, mucosal CD4 T cells phenotypically resembled those in the primary infection, except for the appearance of a PD-1+ subset. Mucosal CD27low Ly6Clow and splenic CD27lowLy6Clow or high CD4 T cells either produced both IFN-γ and IL-2 or IFNγ alone and little IL-17 was detected. These results indicated that antigen-specific intestinal effector and memory CD4 T cells were phenotypically and functionally distinct from their lymphoid counterparts. Furthermore, the distinct phenotype of mucosal memory CD4 T cells implied that these cells may not recirculate. The generation of mucosal memory CD4 T cells in response to oral infection suggested a potential protective role for these cells in maintaining barrier infection.