bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mantle Cell Lymphoma induced reduction of human NKT cells (162.25)
Authors: Sun Wenji , Kimball Amy , Xu Yan , Brutkiewicz Randy , Strome Scott , Webb Tonya 
Published: January 2023

Abstract
Natural killer T (NKT) cells are important in regulating immune responses against tumors. However, patients with mantle cell lymphoma (MCL), an aggressive subtype of Non-Hodgkins Lymphoma (NHL), have a reduction in both NKT cell number and function. We have found that NKT cells from MCL patients fail to be activated by autologous B cells, even in the presence of α-Galactosylceramide (α-GalCer), a potent activator of NKT cells. NKT cells from MCL patients had a significant reduction in their expansion potential and in cytokine production. Compared to serum from healthy donors, MCL serum induced chronic NKT cell stimulation and a rapid upregulation of PD-1 in cultured primary NKT cells (from healthy donors), resulting in an exhausted or anergic phenotype. Mass spectrometry demonstrated the presence of higher levels of sphingosine 1-phosphate (S1P) in patient sera compared to healthy controls sera. The functional involvement of S1P in NKT activation was supported by restoration of the anti-tumor function of NKT cells against MCL following S1P1 signaling blockade. These data suggest that tumor-related induction of S1P production and/or S1P signaling in MCL patients can inhibit NKT cell function, ultimately resulting in reduced anti-tumor responses.
IL-17D mediated cancer rejection (162.26)
Authors: O'Sullivan Timothy , Saddawi-Konefka Robert , Bui Jack 
Published: January 2023

Abstract
Immune system interaction with cancers can either enhance or prevent tumor formation. Cytokine secretion by immune infiltrates and tumor cells are important in regulating this process. IL-17A, a pro-inflammatory member of the IL-17 family, has been shown to have conflicting results in regards to cancer progression or regression. Other members of the IL-17 family, such as IL-17D, have no known roles in immune responses to cancer, or endogenous function. Our lab possesses matched methylcholanthrene (MCA)-induced tumor cell lines that will continuously grow (Progressors) or reject (Regressors) after transplantation into syngeneic WT mice. The regresssor cell lines can grow in immune-deficient RAG2-/- mice, indicating that their rejection in WT mice requires an intact immune system. Our lab has used these cell lines to identify differential cytokine expression profiles from microarray analysis. We have obtained data that shows IL-17D transcript and protein are significantly overexpressed in regressor cell lines when compared to progressor cell lines. Overexpression of IL-7D in progressor tumor cell lines leads to their rejection in WT mice in a NK cell dependent manner. We hypothesize that IL-17D expression in regressor cell lines leads to immune-mediated tumor rejection by recruiting NK cells that polarize M1 macrophages in the tumor microenvironment.
MyD88 and Stat3 signaling are fundamental to tumor associated macrophage function (162.34)
Authors: Qualls Joseph , Neale Geoff , Haverkamp Jessica , Kratochvill Franz , Smith Amber , Balouzian Liza , Roussel Martine , Lahti Jill , Dyer Michael , Murray Peter 
Published: January 2023

Abstract
Macrophage infiltration of solid tumors correlates with poor prognosis for cancer patients. However, the tumor associated macrophage (TAM) phenotype appears complex and does not emulate the current in vitro paradigms of macrophage activation. To determine TAM phenotypes from a variety of solid tumors from distinct organ types, we analyzed global TAM gene expression profiles. &gt; 90% of all gene expression was similar between TAMs isolated from gliomas, thymomas and spontaneously occurring neuroblastomas in mice, suggesting TAMs have a common phenotype regardless of tumor type or location. Importantly, many of the genes with the highest observed expression are involved in macrophage-mediated regulation of the inflammatory response. We have collected gene expression data from TAMs impaired in IL-1 and TLR signaling (Myd88-/-) and observed a MyD88-depedent regulation of multiple secreted proteins involved in Stat3 signaling (IL-6, IL-10, G-CSF) and T cell functional differentiation (IL-23p19, IL-12p40, IL-12p35). Harvesting macrophages from genetic mouse models, we have developed an in vitro neuroblastoma sphere/TAM tissue culture system to define the autocrine/paracrine mechanisms involved in both MyD88- and Stat3-dependent signaling networks, ultimately leading to defining their involvement in T cell differentiation and/or function. Our data will clarify the tumor/TAM relationship and potentially reveal TAM-specific targets for future therapeutic application.
Regulation of invariant natural killer T cell anti-tumor responses by the adaptor molecule Signaling Lymphocytic Activation Molecule-associated protein (SAP). (162.47)
Authors: Das Rupali , Bassiri Hamid , Banerjee Pinaki , Guan Peng , Wiener Susan , Orange Jordan , Nichols Kim 
Published: January 2023

Abstract
Invariant natural killer T (iNKT) cells comprise a unique sub-lineage of innate-like T lymphocytes that participate in anti-tumor immune surveillance. However, several questions remain regarding the mechanisms by which these cells mediate killing of tumor cells. We observe that primary murine iNKT cell cytotoxicity against tumor cells is T cell receptor (TCR)-dependent and requires target cell presentation of iNKT cell-directed agonistic lipid antigens. Interestingly, expression of the cytoplasmic adaptor molecule SAP in primary murine iNKT cells is required for optimal TCR-mediated iNKT cell cytolytic responses towards B- and T-leukemia cells in vitro as well as iNKT cell-mediated control of leukemia cell growth in mice lacking CD8+ T and NK cells. iNKT cell cytotoxicity relies on expression of the Src family tyrosine kinase Fyn, a known SAP binding protein, and on the engagement of SLAM family receptors on iNKT and target cells. Of note, SAP- or Fyn- silenced human iNKT cells exhibit significantly impaired killing of T-leukemia cells in vitro, suggesting that SAP-associated signals are also critical for human iNKT cell anti-tumor cytotoxicity. These studies provide the first mechanistic insights into the signaling mechanisms underlying TCR-induced iNKT cell killing of tumor cells. Studies are ongoing to further elucidate the specific SLAM receptor(s) and downstream signaling mechanisms by which SAP regulates murine and human iNKT cell anti-tumor responses.
Treg cells modulate chemokines and cytokines in lymph node stromal cells (163.11)
Authors: Broggi Maria , Schmaler Mathias , Rossi Simona 
Published: January 2023

Abstract
The LN is composed of stromal cells that form a conduit system and provide a structural environment for homeostasis and differentiation of lymphocytes. We aim to characterize the effect of stromal cells to attract and instruct DC and T cells to initiate immune responses. In our skin transplantation model, Tregs are able to delay the rejection of the allograft in a cell number dependent manner. We isolated stroma cells from LN of mice rejecting (Teff) or tolerating the graft (Teff:Treg). Only in the Teff group, we found lower numbers of TRCs (gp38+CD31-) and higher numbers of double negative cells (gp38-CD31-). Furthermore, TRC from the Teff group down-regulated the production of the chemoattractants CCL19 and CCL21, and different cytokines including IL-7 and FLT3L. The presence of Tregs inhibited the down-regulation or maintained the expression of analyzed molecules. We found that IL-7 increases the suppressive capacity of Tregs in response to alloantigens in vitro. The induction of NOS3 is enhanced in TRCs during graft rejection, which is probably a response to IFNg release in the Teff but not Teff:Treg group. Taken together our results indicate that Tregs influences the expression pattern of stroma cells by inhibiting effector T cells functions in the LN.
Complementary roles of FADD and RIPK3 in T cell homeostasis and antiviral immunity (163.24)
Authors: Lu Jennifer , Weist Brian , van Raam Bram , Marro Brett , Nguyen Long , Srinivas Prathna , Bell Bryan , Keith Luhrs , Lane Thomas , Salvesen Guy , Walsh Craig 
Published: January 2023

Abstract
T cells lacking caspase 8 develop a hyper-autophagic morphology, and succumb to a programmed necrosis-like death process termed necroptosis. RIP kinases RIPK1 and RIPK3 together facilitate necroptosis in response to TNF-α ligation and mitogenic stimulation. We have previously shown the defective proliferation of T cells lacking caspase 8 activity is rescued by crossing with RIPK3-/- mice, and caspase-mediated cleavage of RIPK1/3 necrosis inducing complexes (necrosomes) is sufficient to prevent necroptosis. Enhanced recovery of these double-mutant T cells following stimulation demonstrates that caspase 8 and RIPK3 are essential for clonal expansion, contraction, and anti-viral responses, though such rescue ultimately leads to lymphadenopathy. Enhanced death in wildtype T cells blocked by RIPK1 inihibitor Nec-1 suggests an important physiological role for necroptotic signaling in normal T cells. The NF-κβ pathway plays a key role in regulating T cell death as well, as blockade of NF-κβ signaling results in increased death that can be rescued with Nec-1. This result implicates the role of NF-κβ in regulating levels of sensitivity to necroptosis in CD4+ vs. CD8+ cells. The mechanism of inhibition by NF-κB signaling as well as the spatial and temporal regulation of necrosomes are critical in regulating downstream activating and inhibitory pathways induced during necroptosis.
Down-regulation of ROS-mediated T cell signaling leading to IL-4 production by SOCS targeting ATFII and STAT6 (163.6)
Authors: Lee Choong-Eun , Kim Seol-Hee 
Published: January 2023

Abstract
Suppressors of cytokine signaling (SOCS) have emerged as multiple role players in the regulation of immune signaling pathways. We have recently reported that SOCS1 suppresses ROS-mediated T cell apoptosis through the induction of thioredoxin which down-regulates intracellular ROS levels and protects protein tyrosine phosphatases (Oncogene 28:3145, 2009). In the present study we have investigated the role of SOCS in ROS-mediated T cell differentiation leading to Th1/Th2 cytokine production. Both in Jurkat T cell lines and mouse splenocytes, mild oxidative stress stimulated TCR-mediated cytokine production toward Th2 differentiation: A prominent induction of IL-4 gene expression was noted without notable effects on IFN-r. Such ROS-stimulated TCR signaling for IL-4 induction was mediated by activation of Jak1/STAT6 and p38/ATFII. Introduction and overexpression of SOCS1 and SOCS3 in Jurkat T cells significantly reduced ROS/TCR-mediated IL-4 gene induction with a concomitant inhibition on ATFII and STAT6 pathways. Under this condition SOCS substantially attenuated TCR/H2O2 -induced intracellular ROS levels, suggesting that ROS-scavenging function of SOCS affects TCR signaling leading to IL-4 gene expression. Since we have previously identified human thioredoxin as a Th1-inducing factor in T cells (BMC Immunol 9:64, 2008), the role of thioredoxin in SOCS-mediated down-regulation of Th2 response in conjunction with the regulation of NADPH-oxidase system is under investigation.
The Role of Regulatory T Cells in Determining Outcomes of Chlamydial Genital Tract Infection (164.15)
Authors: Flitter Rebecca , Mintus Margaret , Darville Toni 
Published: January 2023

Abstract
Females are at risk for severe oviduct disease after genital tract infection with Chlamydia trachomatis. Previous studies in our laboratory demonstrate Toll-like receptor 2 (TLR2) activation plays an important role in the development of chronic oviduct pathology after murine chlamydial genital tract infection. Clearance of chlamydial infection has been shown in human and murine investigations to depend on IFN-γ-producing CD4+ T cells. However, an overly zealous adaptive T cell response may contribute to the development of chronic tissue pathology. Pathogen specific T effector cell responses can be suppressed by CD4+CD25+Foxp3+regulatory T cells (Tregs), whose suppressive activity may be abrogated by TLR2 activation. We hypothesize Chlamydia specific TLR2 activation abrogates Treg function resulting in an exacerbated adaptive immune response, which contributes to tissue pathology. Here, we successfully depleted Tregs in a Foxp3DTR mouse model by administration of diphtheria toxin prior to intravaginal infection with TLR2-stimulating Chlamydia murdarium. Although bacterial burden was unaltered, conditional ablation of Tregs resulted in increased IFN-γ-producing CD4+ and CD8+ T cells. Additional studies will determine if removal of Treg suppression leads to increased immunopathology.
Pathogen-specific Th1 cells are activated by IL-1 family cytokines induced by innate stimulation. (164.2)
Authors: O'Donnell Hope , McSorley Stephen 
Published: January 2023

Abstract
Upon antigen recognition, naïve CD4 T cells can develop into effector Th1 cells capable of trafficking to sites of infection and secreting pro-inflammatory cytokines, such as IFNγ. The mechanism of Th1 activation within tissues is often assumed to require additional TCR ligation. However, we have explored whether Th1 cells can be activated by innate stimulation in Salmonella and Chlamydia-infected mice. Using mixed bone marrow chimeric mice, our data show that bacterial-specific Th1 cells can be activated by PAMPs and that production of IFN-γ is dependent upon intrinsic expression of MyD88, but not intrinsic TLR4. Furthermore, loss of IL-18R and IL-33R reduces the ability of Th1 cells to produce IFN-γ, while IL-1R and IFN-γR are not required. Th1 cells were also activated in vitro by IL-1 family cytokines and IL-12, demonstrating that these are sufficient for reactivation. We are currently determining the minimal requirements for Th1 cell stimulation by IL-1 family cytokines and examining the role of this pathway in infection models. Understanding the mechanism and role of innate Th1 stimulation could have widespread implications for understanding antimicrobial and autoimmune pathways.
Regulation of pro-inflammatory Th17 responses during T. cruzi infection by IL-12-family cytokines (164.3)
Authors: Cobb Dustin , Smeltz Ronald 
Published: January 2023

Abstract
Previously we reported that the transcription factor T-bet (Tbx21) regulates Th17 responses to Trypanosoma cruzi infection in an IFN-γ-independent manner. In an effort to further understand this regulation, we examined the development and plasticity of Th17 cells during T. cruzi infection. Th17 cells recovered from infected Tbx21-/- mice were amenable to the inhibitory effects of T-bet, as ectopic expression of T-bet reduced IL-17 expression. We subsequently addressed the role of IL-12 family cytokines IL-12 and IL-27. We report that IL-12p35-/- mice infected with T. cruzi exhibited a significant increase in Th17 cells and peripheral blood neutrophilia, as well as reduced T-bet expression. Ex vivo culture of these cells with IL-12 led to a dramatic reduction in IL-17 production and concomitant increase in IFN-γ. Importantly, the ability of IL-12 to suppress IL-17 was independent of IFN-γ. Surprisingly, IL-27 had no observable effect on Th17 responses to T. cruzi, as infected Ebi-3-/- mice failed to show a significant increase in T. cruzi-specific IL-17 or neutrophilia. Furthermore, IL-27 could not compensate or synergize with IL-12 to suppress IL-17 production ex vivo. Thus, we have established that IL-12, not IL-27, is critical for regulating Th17 responses to T. cruzi.
Cytokine production and cardiac fibrosis in mice reinfected with Trypanosoma cruzi strains (164.8)
Authors: Machado Juliana , Silva Crislaine , Silva Marcos , Borges Diego , Castellano Lúcio , Reis Marlene , Lazo Javier , Ramirez Luis , Rodrigues Virmondes , Rodrigues Denise 
Published: January 2023

Abstract
Introduction: In areas of active transmission of Chagas' disease may occurs reinfection due to repeatedly infections with different T.cruzi strains, but little is known about the immune response induced by reinfections. Objectives: Evaluate the cytokine production and cardiac fibrosis in mice infected and reinfected with T.cruzi strains. Methods: C57BL/6 mice were infected with 3000 trypomastigote forms of T.cruzi (Y strain and Colombian strain). After 90 days, mice from each group were reinfected with the Y strain or with the Colombian strain. A further group were euthanized with only the first infection. After 21 days of the second infection mice were euthanized. The spleen cells were cultured with crude T.cruzi antigen and the cytokines was determined by CBA in culture supernatants. The hearts were removed for measurement of fibrosis. Results: Mice infected with Colombian strain and reinfected with the Y strain showed significantly higher levels of IL-4, IFN-γ and fibrosis. TNF-α was significantly higher in animals infected with the Colombian strain. IL-2 and IL-5 did not show significant difference. Conclusion: The reinfection of mice with the homologous or heterologous T.cruzi strains is associated with modulation of the immune response, as measured by cytokine production by spleen cells in response to antigens of T.cruzi. Modulation of immune response due to reinfection may also interfere on fibrosis formation in the heart tissue in these model of chagas' disease.
Chimeric antigen receptor (CAR) T cell cytokines shape myeloid cell function within the tumor microenvironment and activate host lymphocytes for tumor elimination. (165.4)
Authors: Spear Paul , Barber Amorette , Rynda-Apple Agnieszka , Sentman Charles 
Published: January 2023

Abstract
The infiltration of suppressive myeloid cells into the tumor microenvironment restrains anti-tumor immunity. However, T cell effector cytokines can shape the function of the myeloid lineage to support tumor rejection, regulating the balance between pro- and anti-tumor immunity. In this study, it is shown that effector cytokines secreted by adoptively transferred T cells expressing a chimeric antigen receptor (CAR) shape the function of myeloid cells to promote endogenous immunity and tumor destruction. C57BL/6 mice bearing the ID8 ovarian tumor were treated with effector T cells transduced to express a chimeric NKG2D receptor. GM-CSF produced by the adoptively transferred T cells recruited peripheral F4/80loLy-6C+ cells to the tumor site in a CCR2-dependent fashion. T cell IFN-γ and GM-CSF activated tumor-associated macrophages, increased IL-12p40 production, and augmented antigen presentation by host macrophages to antigen-specific host T cells. In addition, host F4/80+ cells secreted the chemokines CXCL9 and CXCL10 and host T cells were recruited to the tumor site in a CXCR3-dependent manner. Endogenous CD8+ T cells, but not CD4+ T cells, were required for complete tumor elimination. However, host CD4+ T cells were critical for the development of a tumor-specific memory T cell response. These studies show that host macrophages activated by CAR-bearing T cell-derived cytokines inhibited ovarian tumor growth by directly lysing tumor cells and promoting host T cell immunity.
In vivo administration of a novel synthetic GMCSF and IL7 fusion cytokine (GIFT7) leads to transient thymic hyperplasia by driving double-negative (DN), single-positive CD8 (SPCD8) and gamma-delta (γδ) thymocyte proliferation (165.7)
Authors: Hsieh Jeremy , Galipeau Jacques 
Published: January 2023

Abstract
T-cell deficiency secondary to cytotoxic agents, viral assaults or ageing predisposes to defective adaptive immunity. Therefore, therapeutic approaches to enhance thymic output leading to T cell reconstitution are of clinical importance. We develop a novel synthetic fusion cytokine between Granulocyte-macrophage colony stimulating factor (GM-CSF) and Interleukin 7 Fusion Transgene (GIFT7). In vitro, GIFT7 acts as a hyperagonist for the IL7 receptor (IL7R) leading to hyperphosphorylation of STAT5. To test the effect of GIFT7 on IL7R-expressing primary thymocytes, we dissociated normal thymii from C57BL/6 mice and exposed unfractionated thymic cells in vitro to GIFT7 for 5 days. We observed a marked anti-apoptotic and proliferative response in CD3+CD4-CD8+ single-positive CD8 (SPCD8) and CD4-CD8-CD44+CD25- double negative 1 (DN1) T cell precursors in both αβ and γδ T cell lineage. In vivo, intravenous administration of recombinant GIFT7 at 5 µg/kg daily for 2 days into non-irradiated mice leads to a significant 2 fold increase in thymic DN1 population after 7 days. After 14 days, there was a subsequent 100% increase in total thymocyte number which returned to baseline at day 35. We propose the use of GIFT7 as a novel IL7R targeted thymopoietic growth factor for the treatment of catastrophic human immune deficient ailments characterized by thymic involution such as congenital or HIV-mediated acquired immunodeficiency, post-chemotherapy/radiation therapy and ageing.
A novel synthetic GMCSF and IL7 fusion cytokine (GIFT7) overcomes T cell exhaustion leading to central memory T cell formation and promoting peripheral T cell expansion in a PD1-low state (165.8)
Authors: Hsieh Jeremy , Micci Lucca , Silvestri Guido , Paiardini Mirko , Galipeau Jacques 
Published: January 2023

Abstract
T-cell based immunotherapy represents a promising strategy for chronic viral infections or malignancies. However, its efficacy depends on the infused T cell fitness in vivo. Indeed, T cell exhaustion via the upregulation of PD-1 reflects the maladaptive immune response as the root cause of effector cell failure. To address this issue, we report the development of a novel synthetic fusion cytokine between Granulocyte-macrophage colony stimulating factor (GM-CSF) and Interleukin 7 Fusion Transgene (GIFT7). We show that GIFT7 leads to a hyperagonistic response manifest by increased pSTAT5 and proliferation in CD3+/CD127+ cells. GIFT7 also selectively expand a CD8+ subset from pre-activated T cells with a Central Memory phenotype defined as CD8+CD44+CD62L+CCR7+KLRG-CD27+PD1-, hereafter GIFT7CD8. Adoptive transfer of OTI-derived GIFT7CD8 into OVA+EG7-bearing mice leads to a significant anti-tumor effect. Furthermore, GIFT7CD8 persist long-term whilst IL2-actiaved CD8 T-cells are undetected. We also demonstrate the unique expansive effect of the human ortholog of GIFT7 on peripheral blood mononuclear cells (PBMC) derived from non-human primates (NHP) and humans, in that GIFT7 stimulation of pre-activated PBMC leads to T cell proliferation without exhaustion (Ki67hi and PD1low) in CD4+, CD8+, and CD4-CD8- compartments. This observation supports the use of GIFT7 primed T-cells for chronic viral infections or malignancies where an inadequate T cell response is a common feature.