bluuebunny/crossref_metadata_2025_split huggingface dataset:
LIGHT expression in prostate cancer inhibits tumor growth and induces prostate antigen-specific immunity (156.2)
Authors: Yan Lisa , Da Silva Diane , Kanodia Shreya , Gray Andrew , Kast W. Martin 
Published: January 2023

Abstract
An immunosuppressive tumor microenvironment has always been a hurdle for successful immunotherapy even in the presence of induced tumor-specific T cells. Regulatory T cells (Tregs) appear to be key regulators in local immune suppression. LIGHT, a ligand for lymphotoxin-β receptor (LTβR), is predominantly expressed on activated immune cells, signaling via LTβR is required for the formation of organized lymphoid tissues. Forced expression of LIGHT recruits naive T cells into tumors and is capable of establishing tumor specific immunity. However this has never been tested in prostate cancer models where tolerance to self-antigen likely exists. Here we test the hypothesis that forced expression of LIGHT in prostate tumors induces prostate cancer-specific immunity and results in tumor regression by altering the suppressive activity of Tregs and consequently enhancing a more persistent proinflammatory microenvironment. Our data show that intratumoral expression of LIGHT via adenovirus delivery in TRAMP-C2 tumor challenged mice develop de novo CD8+ IFNγ-secreting prostate antigen-specific T cells and display increased survival compared to control treated mice. LIGHT-treated mice also display an increase in ratio of tumor infiltrating lymphocytes to Tregs as well as decrease in Treg suppression activity. Our data suggest that LIGHT treatment can alter the microenvironment such that natural and vaccine-induced prostate tumor antigen specific T cells mediate tumor regression.
mTOR signaling pathway regulates the IL-12/IL-10 axis in Leishmania donovani infection (158.17)
Authors: Cheekatla Satyanarayana , Aggarwal Amita , Naik Sita 
Published: January 2023

Abstract
Macrophage stimulation with TLR ligands and concurrent infection with L. donovani promastigotes results in decreased IL-12 and increased IL-10 production compared to stimulation with TLR agonists. Because mTOR deficiency has been associated with increased IL-12, we hypothesized that host mTOR is central to the evasive effect of parasite on TLR-induced IL-12 inhibition. Here we demonstrate that L. donovani activate mTOR via phosphoinositide 3-kinase/Akt. Parasite enhanced phosphorylation of P70S6K (a correlate of mTOR activity), was completely blocked by rapamycin (mTOR inhibitor). This inhibition resulted in reversal of IL-12, IL-10 production and iNOS expression modulated by the parasite. These observations suggest that mTOR dependent pathway is operative in the modulation of IL-12/IL-10 cytokine axis by the parasite. Parasite internalization by macrophages was not affected by rapamycin treatment, suggesting cytokine reversal mediated by rapamycin is independent of parasite entry. Further blocking TLR2 resulted in the reversal of leishmania-induced IL-10 production. Collectively, these findings provide new insight into the mechanism controlling modulation of IL-12 & IL-10 cytokines by leishmania involving the intracellular network of mTOR pathway in a TLR2-dependent manner. mTOR inhibitors may be an attractive molecule to reverse cytokine modulation and control the infection.
Degeneracy analysis of T cell receptors in mice. (160.17)
Authors: Buntzman Adam , Vincent Benjamin , Krovi S.Harsha , Steele Shaun , Walsh Jesse , Kepler Thomas , Frelinger Jeffrey 
Published: January 2023

Abstract
The potential T cell receptor (TCR) diversity in mice is presumed to be vast. Each mouse contains a small sampling of the possible TCR variants that can be generated, therefore the likelihood that multiple mice generate the same TCR is low. Yet TCR clones have been observed in the memory and naive T cell populations in multiple mice. A global analysis of the inter-mouse TCR repertoire overlap may shed light on a mechanism for the synthesis and retention of shared TCRs. One current model of TCR sharing between mice is based on the hypothesis that degeneracy exists in the TCR recombination machinery at multiple levels. Degeneracy can exist at the recombination level, at the codon usage and amino acid level, at the TCR nucleotide level and at the TCR protein level. This degeneracy has been proposed to drive the generation of TCRs at a higher frequency in each mouse, thus leading to a higher probability of being shared between mice. To globally address whether degeneracy and relative TCR frequency are correlated with the extent of TCR sharing, we have sequenced hundreds of thousands of TCR beta chains from the cytotoxic T cell population of multiple mice and have analyzed the multi-level degeneracy and frequency profile of the shared and unshared pools of TCRs. Our approach provides the first analysis of TCR sharing between mice in whole repertoire.
Chronic differentiation of human mucosal IgA-secreting cells during B cell depletion therapy with rituximab. (161.3)
Authors: Mei Henrik , Frölich Daniela , Giesecke Claudia , Loddenkemper Christoph , Reiter Karin , Schmidt Stefanie , Feist Eugen , Daridon Capucine , Tony Hans-Peter , Dörner Thomas 
Published: January 2023

Abstract
During mucosal immune responses, IgA-secreting plasmablasts are generated from mucosal B cells. We previously demonstrated that at steady-state, most human peripheral blood antibody-secreting cells produce IgA and express mucosal homing receptors, and suggested their generation in mucosal immune responses. In the current study, we analyzed the blood of patients who received B cell depletion therapy with rituximab (anti-CD20) for treatment of rheumatoid arthritis before and at 2-9months after rituximab infusion by flow cytometry. While CD20+ B cells were reduced to &lt;0.02% of their intial numbers before therapy, CD19+/CD27hi/CD20- antibody-secreting cells remained detectable in the blood at 26-119% of their initial numbers. These circulating antibody-secreting cells expressed IgA that bound to bacterial antigens, beta7 integrin and CCR10 before and during B cell depletion, suggesting their mucosal origin. High expression of HLA-DR and Ki-67 and in vitro migration towards CCL28 and CXCL12 qualified these cells as recently activated plasmablasts, reflecting the survival of functional B cells during rituximab treatment. Consistently, IgA+ plasmablasts and plasma cells were identified in the lamina propria during B cell depletion. Our data implicate that a population of mucosal B cells is resistant to rituximab and self-sufficient in adult humans and not replenished by CD20+ B cells immigrating from blood, lymphoid tissue, or bone marrow, that is, B cells depleted by rituximab.
The role of Gr1int interstitial cells in lung host defense against gram-negative bacterial infection. (162.8)
Authors: Poe Stephanie , Arora Meenakshi , Oriss Timothy , Krishnamoorthy Nandini , Yarlagadda Manohar , Ray Anuradha , Ray Prabir 
Published: January 2023

Abstract
We have recently identified a CD11b+Gr1intF4/80+ (Gr1int) regulatory, non-migratory, cell type in the lung that is able to suppress a Th2 effector response via secretion of IL-10, arginase 1 and nitric oxide (NO). These regulatory cells also secrete IL-6 and GM-CSF, but low levels of IL-12. Our studies show that although Gr1int cells are present in the lung of naïve mice, their frequency increases following LPS exposure in a TLR4/MyD88 dependent fashion. The rapid appearance of these cells in response to a TLR ligand, combined with their non-migratory nature and their anatomical location in the lung interstitium, suggests a unique function during host defense against bacterial infections. Much is already known about the role of alveolar macrophages and neutrophils in host defense against Klebsiella Pneumoniae, however little is known about host defense mechanisms in the lung tissue/interstitium. For the first time, we have examined the role of Gr1int interstitial cells in defense against K. Pneumoniae. We show that the Gr1int cell population increases following exposure to K. Pneumoniae, are highly phagocytic, and co-localize with K. Pneumoniae, suggesting phagocytic uptake in vivo. Furthermore, Gr1int secrete high levels of NO, previously shown to be critical for effective innate immunity against K. Pneumoniae.
The balance between autoimmune thyroiditis and cancer immunotherapy (164.6)
Authors: Kari Suresh , Flynn Jeffrey , Zulfiqar Muhammad , Snower Daniel , Kong Yi-chi 
Published: January 2023

Abstract
Clinical trials of immunotherapeutic agents for both autoimmune diseases and cancer often lead to opportunistic autoimmune disorders, where highly prevalent autoimmune thyroid disease is prominent. To simulate cancer patients undergoing immunotherapy, we established a tumor protection model in experimental autoimmune thyroiditis (EAT)-susceptible CBA/J (H2k) mice. Strong tumor immunity required both regulatory T cell (Treg) depletion and immunization with irradiated tumor cells from spontaneous CBA mammary adenocarcinoma line (A22E-j). All mice withstood initial and repeat lethal tumor challenge; protection was mediated by CD4 & CD8 T cells. In EAT, Treg depletion also increases the incidence and severity when immunized with mouse thyroglobulin (mTg), 16x over 4 wks, without adjuvant; soluble mTg mimics physiologic release of circulatory Tg. When combined, EAT was enhanced in mice protected from lethal tumor challenge. To simulate tumor patients with pre-existing autoimmunity undergoing immunotherapy, we induced EAT with mTg + IL-1β (d -29,-22), followed by Treg depletion (d -14,-10), tumor vaccination (d -7,0), lethal challenge (d 0) and soluble mTg (d 0-24, 16x). This regimen had no effect on established EAT and ~75% mice withstood tumor challenge (d 35). The data suggest that ongoing EAT is not affected by induction of tumor immunity, yet tumor immunity may be tempered. Whether subclinical autoimmune disease could be exacerbated by such therapy remains to be determined.
Rewiring of the PKCβII and the Bcr/Abl signal transduction pathways (165.37)
Authors: Hoekstra David , Carlson Louise , Louise Kelvin 
Published: January 2023

Abstract
Chronic myeloid leukemia (CML) accounts for 20% of adult leukemias, and is characterized by the presence of the constitutively active tyrosine kinase Bcr-Abl. Its presence is essential for CML blast survival even in advanced disease, and underlies the success that the Bcr-Abl kinase inhibitor imatinib has had. However, resistance to imatinib occurs in a significant number of accelerated phase or blast crisis patients. Instead of trying to inhibit Bcr-Abl signaling, we propose a previously unexplored approach to rewire signaling pathways to activate proteins that would not normally be activated by Bcr-Abl. We have previously shown that activation of Protein kinase C isoform βII (PKCβII) drives dendritic cell differentiation in normal and leukemic cells. We hypothesized that inserting the Abl kinase motif into a specific domain of PKCβII, would allow Bcr-Abl to activate PKCβII. Using molecular modeling techniques, we have shown that the modified PKCβII pseudosubstrate sequence is largely unchanged as a result of this mutation and still able to respond to traditional activating signals. Additionally, our modified PKCβII is activated in Bcr-Abl+ but not in Bcr-Abl- cells resulting in a decrease in viability and increase in apoptosis. Future experiments plan to characterize the immunogenic potential of these converted leukemic cells, and to fuse the protein transduction domain from HIV onto our modified PKCβII to test the efficacy of this modified protein in a murine model of CML.
Involvement of Axl receptor tyrosine kinase in the pathogenesis of DSS-induced IBD (166.14)
Authors: Ji Kon-Young , Kim Dong-Hern , Kang Hyung-Sik 
Published: January 2023

Abstract
To elucidate the role of Axl receptor tyrosine kinase on the pathogenesis of inflammatory bowel disease (IBD), IBD-associated prognostic factors were examined in dextran sulfate sodium (DSS)-treated wild type and Axl-/- mice. We found that body weight and colon length were decreased in DSS-treated Axl-/- mice compared to those in DSS-treated WT mice. In addition, the reduced number of regulatory T cells was observed in the large intestine, mesenteric lymph node, and peritoneal cavity of DSS-treated Axl-/- mice. Expression of the proinflammatory cytokines was overexpressed in the large intestine of DSS-treated Axl-/- mice. These results suggest that the overexpression of proinflammatory cytokines may be due to the reduced number of regulatory T cells by Axl deficiency. Taken together, it suggests that Axl may be involved in the pathogenesis of IBD, and the regulation of its signaling may be helpful to ameliorate the progression of IBD.
Genes encoding Th2 cytokines and other proteins of immunological interest in the Oryctolagus cuniculus (rabbit) whole genome sequence and ENCODE (170.20)
Authors: Mage Rose , Schäffer Alejandro , Gertz E. , Agarwala Richa 
Published: January 2023

Abstract
Rabbits, a valuable resource for diagnostic and therapeutic antibodies, are becoming increasingly important for vaccine development, and are used as animal models of human autoimmune, infectious and other diseases. The unique characteristics of their immune system, resulting in antibodies of high affinity and specificity, make them a major source of polyclonal and monoclonal antibodies. Whole genome sequencing (WGS) at 7x coverage and assembly of a high quality draft rabbit genome sequence was recently completed at Broad Institute. The Thorbecke Rabbit (TR) chosen for sequencing was less heterozygous than outbred New Zealand White (NZW), but was heterozygous at the immunoglobulin heavy chain locus. The TR strain was more susceptible to Tuberculosis and had obvious developmental abnormalities. Any follow-up on the biology must use another rabbit strain because the TR strain was lost in a fire. The ENCODE Project, with ~ 1% of rabbit genomic sequence from a different, normal NZW animal, includes genes of immunological interest such as a cluster containing the coordinately regulated Th2 cytokine genes IL5, IL13, and IL4. Cross-species comparative genome analysis revealed conservation of some coding and regulatory sequences within syntenic regions of rabbit and 9 other mammals. A few differences between the coding sequences of one TR and one NZW rabbit, and many differences in regulatory sequences across mammals were found. Other genes of the immune system are now under study.
A novel class of host-derived etiological agent for autoimmunity: oligomers of endogenous proteins bind to self-nucleic acids and trigger type I IFN production by plasmacytoid dendritic cells (44.2)
Authors: Di Domizio Jeremy , Zhang Ran , Zhuo Ming , Stagg Loren , Ladbury John , Gilliet Michel , Cao Wei 
Published: January 2023

Abstract
Under certain conditions, some soluble endogenous proteins can form ordered oligomeric structures leading to the assembly of stable insoluble amyloids, a process that increases with age. The presence of such structures is associated with cellular toxicity and diseases development, e.g. Alzheimer disease, type II diabetes. Recent studies clearly show that the primary toxic species in such pathologies is the soluble oligomers of proteins, precursors of amyloids. Yet, it is unknown if such aberrant forms of proteins would elicit any immune reaction. Here we obtained oligomers derived from several human endogenous proteins and characterized their biochemical and immunological functions. The oligomeric proteins preferentially bind to both DNA and RNA and can be effectively internalized by cells. Surprisingly, the soluble protein oligomers enable prominent IFNα production by PBMCs to self-DNA, self-RNA and necrotic cell debris in a pDC-dependent manner. Consistently, peptides from amyloid β and prion protein, two known etiological agents associated with amyloid diseases, display similar innate immune functions by complexing with nucleic acids and inducing IFN production by pDCs. Therefore, oligomers of endogenous proteins formed during the aging process may strongly promote the host’s type I IFN response to self-nucleic acids, a reaction likely favoring the development of autoimmunity, such as SLE where strong type I IFN presence correlates with disease pathology.
Granulocyte expansion and mobilization following EAE induction is correlated with G-CSF production. (44.43)
Authors: Rumble Julie , Rao Praveen , Segal Benjamin 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis (EAE) is a murine model of neuroinflammatory demyelination that is frequently used as a model for multiple sclerosis (MS). EAE is induced mice by immunization with a myelin epitope and adjuvants. We have previously shown that granulocytes are critical for blood-brain-barrier (BBB) breakdown and clinical disease in EAE. In the current study we investigated the pathways by which granulocytes are regulated during EAE. We found that granulocytes expand in the bone marrow and the bloodstream by day 3 p.i., which was preceded by a spike in systemic levels of G-CSF, a granulocyte growth and mobilization factor. Administration of Bordetella pertussis toxin (BPT) is required for the clinical manifestation of disease in our model. Interestingly, sustained expression of G-CSF and accumulation of circulating granulocytes only occurred in mice given BPT. Treatment of immunized mice with an antagonistic G-CSF receptor-Fc fusion protein prevented clinical EAE. We postulate that induction of G-CSF drives the expansion and mobilization of bone marrow-derived granulocytes that ultimately mediate BBB breakdown and subsequent CNS infiltration by leukocytes. Consistent with our findings, individuals with MS experienced severe exacerbations upon the administration of recombinant G-CSF following bone marrow transplantation. Furthermore, we suggest granulocyte growth and mobilization factors as novel therapeutic targets in autoimmune demyelinating disease.
Limiting HCDR3 diversity abrogates the antibody response to the bacterial polysaccharide α 1→3 Dextran (45.20)
Authors: Mahmoud Tamer , Schroeder Harry , Kearney John 
Published: January 2023

Abstract
Anti-polysaccharide antibody responses in mice are often oligoclonal and the mechanisms involved in the production and subsequent antigen-driven selection of these clones are poorly understood. In this study, we investigated the α 1→3 Dextran (DEX) antibody response of gene-targeted mice limited to the usage of one DH gene segment (D-limited mice). We show that the DEX-specific antibody response is broadly comparable in D-limited mice to that of wild type BALB/c (WT) mice. D-limited mice forced to use DH reading frame 2 (ΔD-DµFS) showed both a higher total anti-DEX antibody response compared to other D-limited mice and the dominant DEX-specific J558 idiotype (Id) was higher compared to all mouse groups. Nucleotide sequencing of HCDR3s of DEX-specific plasmablasts showed that ΔD-DµFS mice generated 70% of clones similar to those from WT, including the predominant adult molecularly-determined clone J558. All three D-limited mouse groups showed a higher frequency of unusual DH-less HCDR3 regions compared to WT suggesting extensive junctional modification mediated by TdT. D-limited mice on TdT-deficient background failed to elicit a response to DEX. Overall, these data show that TdT activity is required to compensate for constraints on HCDR3 diversity for the generation of a normal anti-DEX antibody response by D-limited mice.
Defining the molecular and cellular niche for CD8 memory T cell maintenance by 4-1BB and 4-1BBL (46.18)
Authors: Lin Gloria Hoi Ying , Snell Laura , Wortzman Michael , Vidric Mariana , Surh Charles , Watts Tania 
Published: January 2023

Abstract
Following the resolution of an infection, memory lymphocytes can persist for the lifetime of the animal and play a critical role in protection from re-infection. Using mixed BM chimeras, we show that 4-1BB on the T cells is required for maximal CD8 memory T cell response to influenza virus. 4-1BB is constitutively expressed on a fraction of CD8 memory T cells in the BM of unmanipulated mice, with much lower expression in the spleen and LN. The common gamma chain cytokines IL-2, IL-15, and IL-7 can each induce 4-1BB expression on CD8 CD44Hi cells in the absence of Ag ex vivo. However, using CD122-/- mixed BM chimeras and IL-7Ra antibody blockade, they were found to be dispensable for in vivo expression of 4-1BB on memory CD8 T cells. In contrast, the TNFR family member GITR plays a non-redundant role in inducing 4-1BB expression on CD8 memory T cells. 4-1BBL can be detected on CD11c+ cells in the spleen and BM and on CD45 negative cells in the BM. We found that 4-1BBL on radioresistant cells provides the major source of 4-1BBL to maintain the CD8 memory T cell pool detected in the BM, whereas the absence of 4-1BBL on radiosensitive cells makes an additional contribution to the CD8 memory pool detected in the spleen. This study defines a specific niche in the BM, where 4-1BB is expressed on CD8 memory T cells in a GITR-dependent manner and 4-1BBL on a radioresistant CD45 negative cell in the BM provides the source of ligand for 4-1BB-dependent memory CD8 T cell maintenance.
Gliomas display complex cell surface topographies that resist cytolytic lymphocytes but are reversed by using fascin siRNA (48.2)
Authors: Jadus Martin , Hoa Neil , Ge Lisheng , Kuznetsov Yurii , McPherson Alex , Cornforth Andrew , Ahmed Nabil , Lamb Lawrence 
Published: January 2023

Abstract
Gliomas are invasive cancers that resist all forms of attempted therapy, but immunotherapy has improved survival for some patients. We present evidence that another level of complexity may also contribute to lack of responses by the lymphocytes towards gliomas. Atomic force microscopy of four different glioma types: human U251 and rat T9 and F98 glioma cells, including freshly isolated human GBM neurosphere cultures (containing “stem cell-like cells’), revealed a complex surface topography with numerous microvilli and filopodia. These structures were not found on other cell types. Electron microscopy and immunofluorescence microscopy of glioma cells confirmed that microvilli are present. U251 cells with microvilli resisted the cytolytic actions of different human effector cells, (lymphokine-activated killer cells, γδ T cells, conventional cytolytic T lymphocytes, [CTL], and chimeric antigen receptor redirected T cells) better than their non-microvilli expressing counterparts. Killer cells released perforin which was detected within the glioma’s microvilli/ filopodia, indicating these structures can receive the cytolytic effector molecules, but cytotoxicity is suboptimal. Transfection of fascin siRNA into U251 cells prevented the microvilli from forming and allowed cytolytic cells to kill these adherent cells just as well as the non-attached glioma cells. These microvilli play multiple roles in glioma biology, such as invasion and resistance to lymphocyte-mediated killing.