bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancement of DC vaccine efficacy via regulation of interleukin-6 receptor signaling (66.2)
Authors: Choi Inhak , Hwang Wonchan , Jung Keunok , Jean You-Kyoung 
Published: January 2023

Abstract
Tumor microenvironment has emerged as one of the major obstacles against the clinical efficacy of dendritic cell (DC) vaccines. Tumor-derived IL-6 inhibits DC maturation, leading to suppression of T cell-mediated immune response. Based on the findings showing that infusion of blocking anti-IL-6 mAb regressed tumor growth, we reasoned that knockdown of IL-6 receptor signaling could improve the capacity of DC vaccine in tumor-specific T cell activation. We injected mice with a cervical cancer line TC-1 that are expressing human papilloma virus-16 E7 oncogene and IL-6 in vivo, and immunized them with E7 peptide-pulsed bone-marrow-derived DC (BMDC) transfected with IL-6Rα siRNA (siIL-6Rα DC) or treated with IL-6 receptor signal competitor (IL-6RC DC). TC-1-bearing mice immunized with siIL-6Rα DC or IL-6RC showed an obvious decrease in tumor growth and prolonged survival compared to the control mice. siIL-6Rα DC and IL-6RC DC vaccines significantly enhanced the frequency of tumor-specific CD8+ CTLs- producing effector molecules such as IFN-γ, TNF-α, FasL, perforin, and granzyme B, and generated more CD8+ memory T cells. Our results suggest that DC vaccine with regulation of IL-6R signaling may potentiate the therapeutic efficacy of conventional DC vaccines.
Establishment of a positive feedback between PGE2 and COX2 diverts DC differentiation into MDSCs and sustains their immunosuppressive functions in ovarian cancer (66.28)
Authors: Obermajer Natasa , Muthuswamy Ravikumar , Lesnock Jamie , Edwards Robert , Kalinski Pawel 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs) are essential players in cancer-associated immune dysfunction. We report that the differentiation and functional stability of human monocytic MDSCs is driven by a single cancer-associated inflammatory mediator, prostaglandin E2 (PGE2), and depends on the establishment of a positive feedback between PGE2 and COX-2. PGE2 abrogates the differentiation of CD1a+ DC from monocytes, redirecting it towards CD14+CD33+CD34+ cells expressing all MDSC-associated suppressive factors, and inducing their CTL-suppressive functions. Moreover, PGE2 promotes the expression of endogenous COX2 in MDSCs, establishing a positive feedback loop that stabilizes the MDSC phenotype. The frequencies of CD11b+ CD33+ MDSCs in the ovarian cancer (OvCa) ascites correlate with the local production of PGE2, while the OvCa ascites environment can promote the induction of MDSCs from differentiating monocytes in a COX2-dependent manner. Importantly. disruption of COX2-PGE2 feedback in fully-developed MDSCs isolated from cancer patients, using COX2 inhibitors or inhibitors of EP2/EP4-dependent PGE2 signaling, eliminates the production of all other suppressive factors and terminates the CTL-suppressive function of MDSCs. The key role of the positive COX2-PGE2 feedback loop in the differentiation and functional stability of MDSCs facilitates the targeting of MDSCs in cancer immunotherapy.
Impaired antigen presentation and potent phagocytic activity identifying tumor-tolerant human monocytes: demonstration in isolated cells from Mature B-cell neoplasms. (66.47)
Authors: Fernandez-Ruiz Irene , Jurado Teresa , Siliceo Maria , Soares-Schanoski Alessandra , Gomez-Piña Vanesa , Lopez-Collazo Eduardo 
Published: January 2023

Abstract
Monocyte exposure to tumor cells induces a transient state in which these cells are refractory to further exposition to cancer. This phenomenon, termed “tumor tolerance”, is characterized by a decreased production of proinflammatory cytokines in response to tumors. We have established a human model of tumor tolerance and have observed a marked downregulation of MHCII molecules as well as the MHCII master regulator, CIITA. These cells combine an impaired capability for antigen presentation, with potent phagocytic activity and exhibit an M2-like phenotype. We also show that circulating monocytes, isolated from patients who suffer from mature B-cell neoplasm, share all the determinants that characterize cells locked in a tumor tolerance state. In addition, lymphocytes from these patients and supernatants from their in vitro culture, induced a tumor tolerance state in control monocytes. Finally, our results indicated that both, serum from mature B-cell neoplasm patients and supernatants from tumor cells exhibit high levels of Hyaluronic Acid in contrast to control serum from healthy voluteers. Hyaluronic Acid was able to induce a tumor tolerance phenotype in human naïve monocytes.
Role of acute B cell response in dengue disease severity and long-term immunity (67.19)
Authors: Montoya Magelda , Simona Zompi , Pohl Marie , Balmaseda Angel , Harris Eva 
Published: January 2023

Abstract
The four serotypes of dengue virus (DENV) cause dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), the most prevalent mosquito-borne viral disease in humans. Little is known about the acute B cell response during DENV infection and its impact on the breadth and quality of the long-term humoral response. We have measured by flow cytometry the percent of naïve, memory B cells and plasmablasts (PB)/plasma cells (PC) in fresh whole blood from acutely infected patients from a hospital-based study in Managua, Nicaragua. DENV-positive cases demonstrate a significant increase in PB/PCs as compared to DENV-negative cases. The percent of PB/PC in DENV-negative samples ranges from 0.004-5.44% (mean 0.6 +/- 0.19; n=40) compared to 0.04-7.68% (mean 1.5 +/- 0.21; n=83) in DENV-positive samples (p=0.003). No significant difference was found among naïve and memory B cell compartments. Serum avidity is greater in secondary as compared to primary DENV infections. The percent of PB/PC at day 5 post-onset of symptoms appears to positively correlate with serum avidity as measured by ELISA at convalescence (r2=0.83, p=0.015). These data will be correlated with the number of DENV-specific Ab-secreting cells (ASC) measured by ELISpot, as well as with disease severity and the DENV-specific neutralization capacities of the serum. This study will set the basis for future studies and could ultimately impact the design of safe and effective dengue vaccines.
Protein energy malnutrition decreases immunity and increases susceptibility to influenza infection. (67.5)
Authors: Taylor Andrew , Vora Keyur , Cao Weiping , Shieh Wun-Ju , Zaki Sherif , Katz Jacqueline , Sambhara Suryaprakash , Gangappa Shivaprakash 
Published: January 2023

Abstract
Protein energy malnutrition (PEM), a common cause of secondary immune deficiency in children, is associated with an increased risk of infection. We investigated the influence of PEM on susceptibility and immune responses to influenza virus infection using a mouse model. Groups of weanling mice maintained on isocaloric diets providing varying levels of protein energy [18%/adequate protein (AP), 5%/low protein (LP), and 2%/very low protein (VLP)] were infected with either 2009 A(H1N1) or laboratory-adapted H1N1 virus and assessed for disease severity and immune responsiveness. We found that compared to mice fed with AP and LP diets, mice maintained on the VLP diet exhibited an increase in virus-induced mortality and morbidity. Mice maintained on the VLP diet demonstrated diminished IFNγ levels and increased virus titer and inflammatory cell types in lung tissue, compared with mice on higher protein content diets. Moreover, groups of mice maintained on the VLP diet showed a lower hemagglutination-inhibition antibody response and reduced total numbers of splenic NP-specific CD8+ T cells compared with mice on higher protein content diets. Following re-feeding of the VLP group with the AP diet, post-infection morbidity, mortality and virus titer were all improved. Our results highlight the impact of protein energy on immunity to influenza infection and suggest balanced protein energy replenishment may be one strategy to boost immunity against influenza viral infections.
CCL21 dependent CD4+ T cell migration plays a role in protective immune responses against Toxoplasma infection in the brain. (99.22)
Authors: Noor Shahani , Nance J. , Lo David , Carson Monica , Wilson Emma 
Published: January 2023

Abstract
The chemokine receptor, CCR7 and interactions with its ligands CCL19 and CCL21 are well known to facilitate priming of T cells in lymphoid tissue. Our data demonstrate upregulation of CCR7, CCL19 and CCL21 in the brain during Toxoplasma gondii infection at a time point coincident with the peak of T cell infiltration in the CNS. CNS resident astrocytes significantly upregulate CCL21 following direct infection with Toxoplasma tachyzoites and in the absence of CCL21, plt/plt mice were less efficient in controlling parasite replication during chronic infection. Although T cells enter the infected brain in a CCR7 independent manner, migration of extravasated CD4+T cells from the perivascular area into the CNS parenchyma is CCL21-dependent. Our data also demonstrate accumulation of CD4+CCR7 expressing T cells in the infected brain. A significant proportion of these CCR7+T cells express memory T cell markers including IL-7R (Interleukin 7 Receptor) and CD103 (tissue resident memory phenotype). These data indicate CCR7-CCL21 interactions play a role in guiding CD4+CCR7+ memory T cell migration in the brain to prevent parasite reactivation and disease. Analysis of the behavior and phenotype of this memory T cell population in the absence of CCR7 or CCL21 will be presented. These data address the potential contribution of CCR7/CCL21 mediated interactions to maximize memory responses in the brain during Toxoplasma infection.
Cellular and soluble requirements for survival of pulmonary infection with virulent Francisella tularensis (99.29)
Authors: Bosio Catharine , Crane Deborah 
Published: January 2023

Abstract
Francisella tularensis is a facultative intracellular bacterium and the causative agent of tularemia. Inhalation of as few as 15 bacteria can cause lethal disease in humans. Development of novel vaccines and therapeutics for tularemia has been hampered by the lack of understanding of what immune components are required to survive infection. Defining requirements of immunity against virulent F. tularensis, such as strain SchuS4, has been difficult since animals typically die within 5 days after exposure to as few as 10 bacteria. To enable reliable identification of the components of the immune system that are important for defense against infection with F. tularensis we developed a convalescent model of tularemia in C57Bl/6 mice. We show that administration of a low dose of antibiotic over the course of 14 days resulted in clearance of SchuS4 from all organs within 21 days, regardless of the route of infection. However, only 60% of mice infected intranasally survived more than 30 days of infection, whereas 100% of mice infected intradermally survived past this time point. Using mice deficient of specific immune components in this model revealed that both T cells and B cells, are necessary to control SchuS4. Similarly, IL-12p40 and IFN-gamma are also critical for host defense against SchuS4 infection. Together this data provides a novel mechanism by which to identify host factors involved in both resolution and exacerbation of tularemia.
Th17 mediated recurrence of virus-induced immunopathology following discontinued FTY720 treatment (105.10)
Authors: Sehrawat Sharvan , Reddy Pradeep , Suryawanshi Amol , Khatri Madhu , Rouse Barry 
Published: January 2023

Abstract
In this report we show that the anti-inflammatory effect of FTY720 is lost on the discontinuation of treatment in Herpes Simplex Virus (HSV-I) induced ocular inflammation. The lesions developed after FTY720 treatment withdrawals were characterized by the predominance of Th17 cells over Th1 cells. Th17 but not Th1 cells expressed higher levels of surface CD103, an integrin that permits migration to inflammatory sites. Furthermore, we demonstrate that CD4+ T cells isolated from FTY720 treated but uninfected mice could be efficiently polarized towards Th17 and Treg but to a lesser extent towards Th1 phenotype. The hyper acute emergence of inflammation in FTY720 treated animals could be slowed down in IL-17RKO mice and upon administration of neutralizing antibody for IL-6, a proinflammatory cytokine involved in the generation of Th17 cells. These results suggested that approaches such as neutralization of proinflammatory cytokines might be considered along with FTY720 if interruption of the therapy is required to achieve the anti-inflammatory effects of the drug.
Pre-existing viral antigens change the dynamics of CTL response to secondary influenza virus infection (105.24)
Authors: Wu Tao , Lee Young-Tae , Bouchard Keith , Cauley Linda 
Published: January 2023

Abstract
Cytotoxic T lymphocytes (CTL) can provide immunity between different strains of influenza virus, but the immunity declines over the course of a few months and does not correlate with the number of surviving virus-specific memory CD8 T cells. We previously found that processed peptide antigens were presented to naïve CD8 T cells in the draining lymph nodes of the respiratory tract until ~2 months after primary influenza virus infection, which helped some activated virus-specific CTL colonize the lung airways between repeated infections. Similar results were obtained with multiple strains of influenza virus, which indicates that antigen-persistence is a common characteristic of this pathogen. Confocal imaging has been used to examine the distribution of virus-specific CTL in vivo as they response to reinfection in the presence and absence of the pre-existing viral peptides. Our data show that residual peptides alter the local inflammatory environment and augment the response to reinfection. The gradual disappearance of the viral peptides may account for the early loss of heterosubtypic immunity.
Generation of protective memory CD8 T cells specific for a retroviral cryptic epitope (105.25)
Authors: Stevens Cynthia , Rutkowski Melanie , Green William 
Published: January 2023

Abstract
Our lab has shown that cytotoxic CD8 T cells specific for immunodominant cryptic retroviral epitopes are capable of protecting against retrovirus-induced disease. LP-BM5 murine retrovirus causes a profound and progressive immunodeficiency in strains of mice that are unable to produce a protective CD8-T cell response. In resistant BALB/c mice, our lab has identified a Kd-restricted LP-BM5 immunodominant epitope, SYNTGRFPPL, within a previously unrecognized alternative open reading frame of the retroviral gag gene. Upon adoptive transfer, CD8 T cells which recognize SYNTGRFPPL mediate an acute, effector-phase response to LP-BM5, but are inefficient at generating long-term immunological memory to LP-BM5-induced disease. Rapamycin, IL-15 and high-dose IL-2 have been shown to increase the generation and survival of memory CD8 T cells. Using the CD8 T-cell adoptive transfer system employed in our lab to demonstrate acute protection to LP-BM5-induced disease, the aim was to engineer a protective, SYNTGRFPPL-specific memory response by including rapamycin, IL-15, or high-dose IL-2 at the in vitro CD8 T-cell expansion phase of adoptive cellular immunotherapy. The optimization of both acute and long-term memory responses via adoptive transfer of protective CD8 T cells specific for cryptic retroviral epitopes has implications for immunotherapeutic treatment of retrovirus-induced disease.
Virus-specific CD62L- memory CD8 T cells are preferentially retained in the draining lymph node following systemic viral infection (105.28)
Authors: McDermott Daniel , Olson Matthew , Varga Steven 
Published: January 2023

Abstract
Lymphocytic choriomeningitis virus (LCMV) induces a systemic infection in mice with virus replication occurring in both peripheral tissues and secondary lymphoid organs. Because of the rapid dissemination of the virus, the secondary lymphoid organs responsible for the induction of the LCMV-specific CD8 T cell response are poorly defined. We show that the mediastinal lymph nodes (MedLN) serve as the primary draining lymph node following intraperitoneal LCMV infection and that the majority of the LCMV-specific CD8 T cells are primed within the MedLN. Following the resolution of the acute infection (i.e. day 34), we observe that the majority of the memory (KLRG-1-CD127+) LCMV-specific CD8 T cells within the draining-MedLN are CD62L- in contrast to the non-draining LNs where the memory LCMV-specific CD8 T cells are predominantly CD62L+. Importantly, this reduced frequency of LCMV-specific CD62L+ memory CD8 T cells in the MedLN is independent of residual antigen. Furthermore, we demonstrate that the prolonged presence of CD62L- CD8 T cells is not a unique feature of the MedLN as a localized LCMV-footpad infection leads to a similar increase of virus-specific CD62L- memory CD8 T cells in the draining ipsilateral popliteal lymph node vs. the non-draining contralateral popliteal lymph node. These data indicate that CD62L- memory CD8 T cells are preferentially retained in the draining lymph nodes for an extended time following the resolution of a systemic viral infection.
Treating retroviral immunodeficiency-associated tumor by CD8 adoptive T-cell therapy (105.29)
Authors: Li Wen , Green William 
Published: January 2023

Abstract
LP-BM5 virus infection in susceptible B6 mice induces a HIV-like immunodeficiency syndrome, termed “murine acquired immunodeficiency syndrome (MAIDS)”. We have previously shown that highly active, LP-BM5-specific CD8 cytolytic T lymphocytes (CTLs) can be raised against LP-BM5-associated B-cell lymphomas through in vivo priming and in vitro restimulation with syngeneic LP-BM5-associated B-cell lymphoma line. Adoptive transfer of such polyclonal anti-LP-BM5 tumor CTLs inhibited the development of MAIDS. To identify new potential immunotherapeutic approaches to promote protective CTL-mediated responses, thus to treat LP-BM5-associated B-cell lymphomas, we examined the effects of specific blockadge of the PD-1 mediated negative signaling pathway in CD8 T cells following tomor inoculation. Adoptive transfer experiments using CD8 T cells from B6.PD-1-/- mice were performed, and then tumor growth, and retrovirus-induced tumor specific effector CD8 T-cell responses were measured. Our results showed that LP-BM5-specific CTL responses were significantly enhanced in mice adoptively transferred with PD-1-/- CD8 T cells than that in miced transferred with wild type CD8 T cells. Tumor growth was also significantly inhibited in mice transferred with PD-1-/- CD8 T cells. Altogether, manipulation of PD-1-associated down-regulation of CD8 T cell responses may provide novel immunotherapies in treating retroviral infection-associated lyphomas.
Increased immune activation during chronic SIV infection drives the TFH dynamics. (105.33)
Authors: Petrovas Constantinos , Yamamoto Takuya , Gerner Michael , Boswell Kristin , Roederer Mario , Seder Robert , Germain Ronald , Haddas Elias , Koup Richard 
Published: January 2023

Abstract
We have investigated the phenotype, location, molecular signature and function of follicular CD4 T helper cells (TFH) in rhesus macaques. Similar to human TFH, they are characterized by a CCR7lowPD-1highICOShighCTLA-4highCXCR4high phenotype and represent a heterogeneous population with respect to cytokine function. PD-1high CD4 cells were localized closer to the follicle center than PD-1low CD4 cells. This relative cellular distribution was not affected by the SIV infection. Production of Th1 cytokines was compromised while IL-4 was secreted predominantly by a highly differentiated (CD150low) subpopulation of TFH cells. Compared to non-TFH cells, TFH cells exhibited a distinct gene profile that was significantly altered by SIV infection. A significant reduction in the expression of the IL-4 gene in TFH was found implying a defective help for the development of B cell responses during chronic SIV. CD150low TFH cells were characterized by defective survival while in vivo BrdU integration studies revealed a defective cycling capacity of these cells. Preferential infection of TFH cells was found only during acute SIV yet progression to chronic SIV resulted in their accumulation, which was associated with high immune activation and altered IL-6-induced signaling. Thus, the preservation of TFH in the face of high rates of infection can be explained by their normally short half-life and the diverse populations of CD4 T cells that can provide to their continual replenishment.
Effects of Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) on cytokine production in primary and transformed B cells (105.40)
Authors: Swanson-Mungerson Michelle , Incrocci Ryan , McCormack Molly , Leof Caroline 
Published: January 2023

Abstract
Epstein-Barr Virus (EBV) latently-infected B cells are precursors of EBV-associated malignancies. However, the transition from a latently-infected cell to a malignant tumor cell is poorly understood. Studies show that EBV modulates pro-survival and anti-inflammatory cytokine levels in EBV-transformed cell lines. However, gene expression in these cell lines may not reflect gene expression found in latent B cells and lymphomas. One EBV protein, LMP2A, is consistently detected in both latently-infected resting B cells, as well as in EBV-associated malignancies. Therefore, we hypothesized that LMP2A may modulate cytokines that aid in the transition between latency and malignancy. Cytokine array data analyzing B cells from LMP2A-transgenic mice and B cell lymphomas expressing LMP2A indicate that LMP2A does not globally alter B cell-produced cytokine levels, but rather targets a limited number of cytokines. Additional studies using ELISA and Real-time RT-PCR confirm that LMP2A increases IL-10 levels and flow cytometry reveals that LMP2A increases the amount of IL-10 produced per B cell. Inhibitors of the LMP2A signaling pathway are being tested to determine the signaling requirements for LMP2A-mediated increases in IL-10. These data identify a novel function of LMP2A in the alteration of a cytokine that is important for both tumor survival and anti-tumor responses.
Premature senescence of circulating T cells in HCV-chronically infected patients (105.41)
Authors: Yu Qigui , Amet Tohti , Byrd Daniel 
Published: January 2023

Abstract
Persistent HCV infection is characterized by chronic immune system activation and inflammatory cytokine production. Thus, HCV infection may result in features characteristic of premature aging of immune cells (immune senescence), driven by chronic antigen exposure and immune system activation. To determine if untreated HCV infection is associated with premature aging of naïve and memory CD4+ and CD8+ T cells, peripheral blood mononuclear cells (PBMCs) from 24 individuals chronically infected with HCV and 13 healthy blood donors were stained with fluorochrome-conjugated antibodies, and then subjected to multiple-color flow cytometric analysis. We found that chronic HCV infection was associated with a decreased CD28 median florescence intensity on both CD4+ (CD3+/CD4+/CD45RA+CD27+CD28+) and CD8+ (CD3+/CD8+/CD45RA+CD27+CD28+) T cells. An increased proportion of intermediate- and late-differentiated CD4+ and CD8+ T cells was also observed in PBMCs from HCV chronically-infected individuals. In addition, higher levels of activated monocytes (CD14+/CD16+ or CD14+/CD69+) were detected in HCV chronically-infected individuals than that in healthy blood donors. Conclusions: The overall change during chronic HCV infection is associated with a shift in the T-cell population toward an aged confirmation. Our data suggest that HCV-infected individuals experience similar immunologic changes as the individuals infected with HIV-1.