bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying an IDO-expressing “fibrocyte” subset of myeloid suppressor cells in pediatric cancer patients. (127.28)
Authors: Zhang Hua , Mackall Crystal 
Published: January 2023

Abstract
Human myeloid derived suppressor cells (MDSC) have been described as CD14-CD11b+CD33+HLADR- cells that exert T cell suppression via ROS, ARG1 and iNOS2. Here, we identify a novel myeloid suppressor subset, expanded in the peripheral blood of pediatric cancer patients, which is CD14-CD11b+CD33loHLADR+. Further analysis revealed that these abnormal myeloid cells were CD34+CD11chiIL4Rα+CD16+, and express α smooth muscle actin and collagen I/V on their surface, hallmarks of fibrocytes. The fibrocytes expressed high levels of indoleamine oxidase (IDO), and suppressed T cell proliferation in response to OKT3, which was partially reversed by the addition of 1MT, an inhibitor of IDO. Given the IL4Rα expression, we sought to induce these cells in vitro from normal monocytes using IL-4. Indeed, IL4 alone was sufficient to drive monocytes to differentiate into fibrocytes, which demonstrate a spindle-like shape, adhere to plastic, acquire the CD14-CD34+CD11chiCD123-CD16+collagenI+ phenotype, and express IDO. Fibrocytes have previously been implicated in chronic inflammation, angiogenesis and wound healing. We conclude that they also constitute a novel subset of myeloid derived suppressor cells in humans, and could contribute to tumor progression.
Imbalance of activating and inhibitory receptor expression on effector cells in multiple myeloma patients results in immune suppression (127.35)
Authors: Hsu Andy , Davenport Alex , Smyth Mark , Ritchie David , Neeson Paul 
Published: January 2023

Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy of the bone marrow (BM). Recent evidence suggests that natural killer (NK) cells are intricately involved in the immunosurveillance of MM and can specifically target malignant plasma cells in the absence of the immunosuppressive BM microenvironment. Immune suppression in MM patients is systemic with total CD4 T cell counts in the peripheral blood significantly lower than healthy donors. We have data showing that the major NK activating receptor NKG2D is significantly reduced in MM patients, whereas inhibitory NKG2A, KIR2DL1 and KIR2DL3 are up-regulated. These inhibitory receptors target HLA-E and C respectively, and dominate over activating signals. Interestingly, we report that NKG2A, KIR2DL1 and KIR2DL3 were also up-regulated on T cells in MM patients. Our subsequent investigations showed that expression of KIR receptors could be induced on CD4 T cells independent of direct cell contact with MM cells. Throughout treatment using an empirical MM drug regimen including an immunomodulatory drug and a corticosteroid, we saw restoration of NKG2D but no change in the expression of inhibitory receptors on NK or T cells in MM patients. Together, this data reveals a novel model of T cell tolerance to MM and highlights to therapeutic potential of KIR blockade to reverse immune suppression.
M2 macrophages express CD1d and are selectively targeted by NKT cells in tumors (127.39)
Authors: Courtney Amy , Liu Daofeng , Wei Jie , Gao Xiuhua , Marinova Ekaterina , Asgharzadeh Shahab , Metelitsa Leonid 
Published: January 2023

Abstract
CD1d-reactive Valpha24-invariant Natural Killer T cells (NKTs) are potentially important for tumor immunity. However, the mechanism by which NKTs mediate antitumor responses against CD1d-negative tumors has remained enigmatic. Recent findings by us and others suggest that instead of attacking tumor cells directly, NKTs may target CD1d-positive tumor-supportive myelomonocytic cells. We have demonstrated that NKTs co-localize with tumor-associated macrophages (TAMs) in primary human neuroblastoma (NB). The phenotypic analysis of TAMs in primary tumors has revealed the existence of both M1- and M2-polarized subsets. However, only the numbers of CD163-positive M2 macrophages correlated with metastatic disease and poor outcome. Importantly, we found that CD1d is selectively expressed on M2, but not on M1 macrophages, both in TAMs isolated from primary NB tissues, and in in vitro polarized macrophages. NKTs mediated CD1d-dependent in vitro cytotoxicity against M2 macrophages or polarized them to an M1 phenotype via soluble mediators. The latter was in part dependent on NKT-derived GM-CSF and IFNγ. Moreover, adoptive transfer of ex-vivo expanded human NKTs resulted in a significant reduction that correlated with anti-metastatic activity. Thus, targeting of tumor-supportive M2 TAMs by NKTs reveals a novel mechanism of tumor immunity that can be exploited for the development of effective immunotherapy of solid tumors.
Interleukin 18 regulated gene, erythroid differentiation regulator 1 acts as metastasis suppressor in murine melanoma. (127.5)
Authors: Jung Min Kyung , Cho Daeho 
Published: January 2023

Abstract
Erythroid differentiation regulator (Erdr1) was first discovered on mouse leukemia cell lines and functions as a stress-related survival factor. This study investigated whether Erdr1 regulates murine melanoma progression, as well as the mechanism involved in Erdr1-regulated metastasis. The expression of Erdr1 is negatively correlated with IL-18 expression which has a pro-cancer effect in melanoma. To study the role of Erdr1 as anti-cancer factor, cell migration and invasion ability were measured. Erdr1 over-expression markedly inhibited the level of cell migration and invasion ability in B16F10 cells, in vitro. Additionally, Erdr1 over-expression significantly suppressed melanoma lung colonization and metastasis, in vivo. In order to indentify the factors involved in Erdr1-reduced metastasis, heat shock protein 90 (HSP90), a well known stress protein and contributor to tumor metastasis, was examined. We found that HSP90 was significantly decreased in Erdr1 over-expressing cells. Functional analysis demonstrated that HSP90 siRNA transfection reduced the migration ability and metastasis of melanoma. In conclusion, Erdr1 shows powerful anti-metastasis effect that leads to ability to reduce the metastatic potential of murine malignant melanoma cells. Erdr1 is a novel anti-metastatic factor and may be a possible therapeutic target for treatment of melanoma.
Lysosomal DNaseII degrades nuclear DNA and prevents self DNA recognition (159.17)
Authors: Lan Yuk Yuen , Londoño Diana , Hacohen Nir 
Published: January 2023

Abstract
The aberrant activation of innate immune sensors by self nucleic acids can foster the development of autoimmunity. For example, the absence of nucleases that degrade self nucleic acids leads to autoimmune diseases in mice and humans. DNaseII is the major lysosomal DNA-degrading nuclease. Its deletion in mice results in the accumulation of self DNA, induction of inflammatory cytokines, and development of chronic polyarthritis that resembles human rheumatoid arthritis. DNaseII is known to degrade extracellular DNA in phagocytes. However, given its ubiquitous expression across cell types, we hypothesized that the nuclease plays a broader role in the clearance of DNA. Supporting this notion, DNA accumulated in both phagocytic and non-phagocytic cells from DNaseII-deficient mice, and could be further elevated by treatment with DNA-damaging agents. Concomitantly, cytokines and other immune genes were upregulated through a Sting-mediated cytosolic nucleic acid sensing pathway. Surprisingly, DNA accumulated within nuclear buds and extranuclear aggregates that often co-localized with autophagic and lysosomal markers. A deficiency in autophagy displayed higher levels of extranuclear DNA and enhanced Sting-dependent innate immune response. The observed nuclear to lysosomal DNA clearance process appears to eliminate discarded nuclear DNA in the steady state and in response to DNA damage, and protect cells and organisms from developing pathological immunity to self DNA.
IL-17-induced Regulator of G-protein Signaling orchestrates germinal center kinetics in the onset of autoimmunity in BXD2 mice (159.24)
Authors: Mountz John , Wang John , New James , Yang PingAr , Wu Qi , Druey Kirk , Hsu Hui-Chen 
Published: January 2023

Abstract
Development of germinal centers (GCs) is a hallmark of BXD2 autoimmunity. We have shown that IL-17+ CD4 cell frequencies are significantly elevated in the spleen of BXD2 mice, leading to the induction of Regulator of G-protein Signaling (RGS) 13 and 16 and decreased sensitivity to CXCL12 and CXCL13. The resulting chemotactic arrest within the GC promotes extensive somatic hypermutation (SHM) mediated by activation-induced cytidine deaminase (AID). Here we explore mechanisms underlying this phenotype using BXD2-Rgs13-/- and BXD2-Rgs16-/- mice. BXD2-Rgs13-/- mice exhibited higher autoantibody titers in early age compared to wild-type (WT) mice though smaller GCs and lower AID levels suggested a lesser extent of SHM and affinity maturation. There was upregulation of IRF4 in B cells of BXD2-Rgs13-/- mice, suggesting these B cells develop into plasma cells more rapidly than WT B cells. At older ages, BXD2-Rgs13-/- mice showed less IgG deposits in the glomeruli, suggesting reduced autoantibody pathogenicity. RGS16 deficiency led to aberrantly localized T cell zones and reduced aggregation of a population of CD86hi marginal zone precursor (MZP) B cells, accompanied by significantly fewer GCs, suggesting a role in localization of MZP in GC light-zone and B-T co-stimulation events. Taken together, these results suggest a unique role for IL-17 in inducing pathogenic GCs and development of autoimmune disease in BXD2 mice through RGS13 and RGS16-dependent pathways.
Early biomarkers of resistance and susceptibility to mycobacterial disease (160.1)
Authors: de Silva Kumudika , Begg Douglas , Plain Karren , Purdie Auriol , Kawaji Satoko , Dhand Navneet , Whittington Richard 
Published: January 2023

Abstract
Mycobacterial diseases such as tuberculosis and paratuberculosis continue to be of serious health and economic concern to humans and livestock globally. Lack of knowledge on the nature of the protective immune response as well as immunological markers of disease susceptibility and latency hamper the development of effective vaccines and other therapies. The use of a well-characterised ruminant infection model enabled us to follow the host response to mycobacterial challenge from the time of exposure until manifestation of clinical disease in a natural host. This study (30 controls and 58 challenged in 2 trials) tracked cellular and humoral responses, and quantity of mycobacterial shedding, for up to 30 months post challenge in sheep. Infection was defined as the presence of viable organisms in tissue sections taken at necropsy. The IFNγ response increased after exposure regardless of disease outcome. Parameters measured could distinguish severely diseased animals from those that had been exposed but were uninfected. Infectious or severely diseased animals were more likely to have a lower IFNγ response early (4 months post exposure) compared to exposed uninfected animals. This latter group were also more likely to have an elevated early IL-10 response. These studies demonstrate the complexity of the immune response to pathogenic mycobacteria and illustrate the fact that measurement of a single immunological parameter is insufficient to determine the outcome of disease.
Cytotoxic T cell epitope in Brucellosis-induced murine spondyloarthropathy shows 100% homology with the host mouse peptide (160.6)
Authors: Adarichev Vyacheslav , Lyons Elizabeth , Magnani Diogo , Forde Toni , Splitter Gary 
Published: January 2023

Abstract
Brucellosis is resulted in spondyloarthropathy (SpA) in almost 50% of human patients, but mechanisms of this association are poorly characterized. To study immune mechanisms of SpA, BALB/c mice were infected with bioluminescent B.melitensis, and bacterial dissemination in spleen, liver and axial skeleton was monitored using bioluminescence and immunohistochemistry (IHC). At the peak of infection, bioluminescence showed accumulation of bacteria in front and hind paws, but the strongest signal was detected in the caudal skeleton reproducing the distribution of vertebrae. IHC confirmed intracellular bacteria in spleen, liver, and in the subchondral bone marrow of vertebrae and in peripheral joints without inflammatory cells infiltration. At 26 weeks post infection, bacteria were cleared from the body, but mice developed ankle joint arthritis and spondylolisthesis. We found that immunodominant Brucella-derived peptide from methionine sulfoxide reductase is presented by murine macrophages in context of MHC class I molecule to cytotoxic T cells (CTL). Homologous mouse/host protein carries a sequence that is 100% identical to Brucella epitope. In silico prediction analysis indicates that Brucella epitope binds to human HLA-B*2705 and B*2702 class I molecules, that are strongly associated with human SpA. Our data provide support for brucellosis-induced SpA as a reactive arthritis-type disease with a potential involvement of CTL in the disease pathogenesis.
IL-33 directly supports the proliferation of suppressive, naturally-occurring regulatory T cells expressing the IL-33 receptor, ST2 (161.1)
Authors: Mathews Lisa , Rosborough Brian , Thomson Angus , Turnquist Heth 
Published: January 2023

Abstract
Overview: Both IL-33 and its receptor, ST2, have been ascribed T helper type-2 (Th2) response promoting capacities. However, IL-33 increases splenic CD4+ forkhead box P3 (Foxp3)+ regulatory T cells (Treg) and post-transplant IL-33 monotherapy mediates a Treg-dependent prolongation of experimental cardiac allograft survival. As such, we addressed whether IL-33 directly targets Treg to support their expansion or suppressive function. Methods: The ability of recombinant IL-33 to facilitate anti-CD3/CD28-stimulated proliferation of BALB/c St2+/+ or St2-/- CD4+ CD25+ T cells was compared to IL-2. Following stimulation, Treg phenotype was defined by flow cytometry and their capacity to suppress naive T cell proliferation determined in bead-based suppression assays. Results: Following 3-4 days of culture, both cytokines promoted significant Treg proliferation vs. CD3/CD28 stimulation alone. However, IL-33 facilitated the expansion of a population ST2+ Foxp3+ cells that were absent from IL-2-treated cultures. Both IL-2 and IL-33-exposed Treg cultures exhibited suppressive activity. Conclusions: We identify the previously unreported capacity of IL-33 for direct expansion of Treg. Also, our data reveal that ST2, in addition to being expressed on Th2 cells, is found on an IL-33-expanded subset of suppressive Treg. These findings have significant implications for the therapeutic use of IL-33 to expand Treg, -cells critically important to tolerance and organ allograft survival.
PCNA: a novel cancer-associated ligand for the NK cell receptor NKp44 (162.10)
Authors: Brusilovsky Michael , Rosental Benyamin , Hadad Uzi , Campbell Kerry , Porgador Angel 
Published: January 2023

Abstract
Natural Cytotoxicity Receptors (NCRs: NKp30, NKp44, and NKp46) trigger NK cell-mediated lysis of tumors and virus-infected cells. Previous studies identified BAT3, B7-H6 and Vimentin as cellular ligands for NKp30 and NKp46, respectively. However, our knowledge of NCR-mediated recognition of cancer cells remains incomplete. NKp44 is expressed exclusively in primates and its expression is induced upon activation of NK cells. We have discovered that NKp44 directly recognizes Proliferating Cell Nuclear Antigen (PCNA), which is recruited within target cells to the NK immunological synapse. Over-expression of PCNA was found to inhibit NK cell cytotoxicity in an NKp44-dependent manner. Also, the cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) in NKp44 is crucial for PCNA-meditated NK cell inhibition. Since PCNA over-expression can promote cancer survival, our study reveals a novel immune evasion mechanism. Our results also further emphasize the role of nuclear proteins as ligands for Natural Cytotoxicity Receptors.
M2b monocytes predominantly appear in patients with advanced hepatocellular carcinoma (HCC patients) (162.29)
Authors: Asai Akira , Tsuchimoto Yusuke , Fukunishi Shinya , Tsuda Yasuhiro , Fukuda Akira , Kobayashi Makiko , Suzuki Fujio , Higuchi Kazuhide 
Published: January 2023

Abstract
In response to tumor environments, resident Mϕ differentiate into M1Mϕ or M2Mϕ. Recently, three different subsets of M2Mϕ (M2aMϕ, M2bMϕ and M2cMϕ) have been reported. Therefore, in this study, the properties and subsets of monocytes isolated from early and advanced HCC patients were characterized. CD14(+) monocytes were isolated from peripheral blood of HCC patients by Ficoll-Hypque sedimentation and magnetic beads. HCC patients, who were confirmed as carriers of hepatic cancer cells, were enrolled in this study. Monocytes (1 x 10(6) cells/ml) were cultured for 48 hrs and culture fluids harvested were assayed for cytokines by ELISA. Tumoricidal activity of monocytes against hepatic cancer cells was assessed using a standard chromium release assay. In the results, monocytes from advanced HCC patients were shown to be M2b monocytes, because they produced IL-10 (188 ± 21 pg/ml) and CCL1 (24 ± 0.6 ng/ml), and did not produce IL-12, CCL17 and CXCL13. Monocytes from early HCC patients were characterized as M1 monocytes, and healthy donor monocytes were determined as resident monocytes. Monocytes from early HCC patients killed syngeneic hepatic cancer cells (73 ± 7%), while monocytes from advanced HCC patients did not (10 ± 3%). These results indicate that advanced HCC patients are carriers of M2b monocytes and early HCC patients are M1 monocyte carriers. M2b monocytes detected in advanced HCC patients may play a role on the decreased host’s antitumor resistances.
Cancer immunoediting by the innate immune system in the absence of adaptive immunity (162.3)
Authors: Saddawi-Konefka Robert , O’Sullivan Timothy , Vermi William , Koebel Catherine , Arthur Cora , White J. Michael , Uppaluri Ravi , Andrews Daniel M. , Ngiow Shin , Teng Michele , Smyth Mark , Schreiber Robert , Bui Jack 
Published: January 2023

Abstract
Cancer immunoediting is the process whereby immune cells protect against cancer formation and sculpt the immunogenicity of developing tumors. The complete process of immunoediting requires both innate and adaptive immunity, but it remains unclear to what extent innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3’methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2-/-, and RAG2-/-x γc-/- mice. We found that innate immune cells could indeed manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required γc and IFNγ, which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2-/-x γc-/- mice. Our results suggest that in the absence of adaptive immunity, natural killer cell production of IFNγ induces M1 macrophages, which act as important effectors during cancer immunoediting.
Ongoing priming of naïve melanoma/melanocyte specific CD8 T cells occurs in hosts with vitiligo (P225) (162.6)
Authors: Byrne Katelyn , Steinberg Shannon , Zhang Peisheng , Turk Mary Jo 
Published: January 2023

Abstract
Vitiligo, the autoimmune destruction of melanocytes, correlates with improved survival in melanoma patients although it is often disregarded as a side effect of robust anti-tumor T cell responses. We have shown that antigen provided by vitiligo is required for long-lived CD8 T cell memory against melanoma-expressed self-antigens. However, the possibility that autoimmune melanocyte destruction itself may prime CD8 T cells able to cross-react against melanoma has not been investigated. Previously, we reported vitiligo development in 60% of mice depleted of regulatory CD4 T cells while bearing established B16 melanoma tumors. To probe the immunogenicity of vitiligo, we transferred naïve melanocyte-antigen specific pmel CD8 T cells in to actively depigmenting hosts. We find that CD8 T cell activation and proliferation occurs in an antigen-specific manner only in hosts with vitiligo. Furthermore, although the pmel cells do not produce IFN-γ, the cells produce Granzyme B and express LAMP-1 and P selectin ligand. Interestingly, although vitiligo-primed CD8 T cells appear strongly activated, the cells do not form robust memory populations in the presence of CD4 T regulatory cells. Ongoing studies aim to investigate the anti-melanoma capabilities of vitiligo-primed CD8 T cells. These studies will further enhance our understanding of the direct relationship between tumor immunity and autoimmunity, and the contributions of these cells in protecting against recurrent tumor growth.
Cholera toxin enhances IL17 production by CD4+ T cells via cyclic AMP signaling pathway (163.5)
Authors: Tsai Hsing-Chuan , Wu Reen 
Published: January 2023

Abstract
Cholera toxin (CT) is one of the most potent mucosal adjuvants. It has been reported to improve antigen presentation as well as suppress resting T cell activation. Recently, CT was also reported to indirectly increase the Th17 response through elevating IL-6 production from dendritic cells. This result suggests a vital role of CT in mucosal immunity. The goal of our study is to understand how cholera toxin modulates the response of CD4 T cells. We found that CT can directly enhance IL-17 production by CD4+ T cells but decrease IFN-γ, TNF-α, IL2, and IL-10 production. In addition, CD4 T cells were treated with different cAMP-elevating agents, including CT B subunit and PKA inhibitors. We found that the effect of cholera toxin on Th17 response goes through a PKA-independent but cAMP signaling dependent pathway. A more detailed study of cAMP signaling is required to fully understand how cAMP signaling controls this Th17 response. Furthermore, CT may also prevent Th17 cells from becoming Th17/Th1 cells which are more pathogenic in Th17-mediated diseases. Whether cholera toxin or cAMP signaling constrains Th17-mediated pathology will be examined.
Time-dependent IFN-γ and CXCL-10 production in tuberculosis patients after the establishment of clinical cure (164.5)
Authors: Silva Marcos , Massaro Júnior Vladimir , Machado Juliana , Castellano Lucio , Rodrigues Denise , Rodrigues Virmondes 
Published: January 2023

Abstract
Introduction: The immune response involved in the establishment of the clinical cure is not fully elucidated in human tuberculosis. The understanding of Th1 cytokines and chemokines role may drive the development of new therapeutic and diagnostic approaches. Objectives: The objective was to evaluate the IFN-γ and CXCL-10 production by BCG soluble antigen-stimulated PBMCs from patients with pulmonary tuberculosis. Methods: Blood samples were collected from 26 TB patients being 12 with active disease, 7 clinically cured patients with less than 12 months of treatment end and 7 with more than 12 months. PBMCs were cultured in RPMI medium alone or stimulated with 2ug/ml PHA or 10ug/ml BCG antigen. The IFN-γ and CXCL-10 production was determined in culture supernatants by ELISA. Results: The TB-treated patients showed significantly higher production of IFN-γ and CXCL-10 in all culture conditions than active disease patients. The augmented production of IFN-γ was mainly observed in clinically cured patients with more than 12 months of treatment. However, the CXCL-10 elevation was observed mainly on clinically cured patients with less than 12 months treatment. Conclusion: These results indicate that the potentiation of IFN-γ and CXCL-10 production occurs at different times after the establishment of clinical cure. This may suggest that the turn toward a Th1 immune response occur later, after clinical cure.