bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemokine-mediated B cell trafficking in rabbit GALT during diversification of the primary antibody repertoire (160.15)
Authors: Lanning Dennis , Knight Katherine 
Published: January 2023

Abstract
Rabbits preferentially rearrange the 3’-most VH gene segment during VDJ gene rearrangement. Early in life, rabbit B cells generate a diversified primary antibody repertoire by mutating their VDJ genes in gut-associated lymphoid tissue (GALT) in response to signals acquired from intestinal commensals. To gain insight into the cell-cell and cell-microbe interactions required for VDJ gene diversification, we examined B cell surface expression levels of four chemokine receptors that mediate trafficking to important sites within GALT during repertoire diversification. We stained the chemokine receptors CXCR4, CCR6, CXCR5 and CCR7 on appendix B cells from two- through seven-day-old rabbits with fluorescence-labeled antibodies or Ig-fusion proteins of their ligands and analyzed them by flow cytometry. The changes in relative chemokine receptor expression levels we observed during the first week of life suggest that B cells, upon entering appendix follicles, first traffic to the follicle-associated epithelium, where they likely encounter commensal bacteria sampled from the intestinal microbiota. B cells subsequently migrate to, and likely receive additional signals from, the follicular dendritic cell network. Upon becoming activated, B cells then traffic to the basal region of the follicle, where they proliferate and diversify their VDJ genes to generate the primary antibody repertoire.
Secretory IgD has an evolutionarily conserved role in respiratory mucosal defense (160.18)
Authors: Bromage Erin , Ramirez-Gomez Francisco , Greene Whitney , Rego Katherine , Hansen John , Boardman Timothy , Dupras Danielle 
Published: January 2023

Abstract
Recently, we discovered secreted IgD in rainbow trout, which is produced by a novel exon-splicing mechanism. Molecular and cellular analysis revealed that secIgD plasma cells were distributed within the primary and secondary immune tissues. The concentration of serum IgD (2-80µg/ml) was ~400x lower than serum IgM (800-9000µg/ml). Two dominant secIgD heavy chain isoforms were identified in serum of trout which were associated with antibody light chains to form 240 or 370 kDa IgD-monomers. Antigen-specific secIgD was produced in response to vaccination with either TI or TD antigens. Interestingly, the distribution of antigen-specific IgD plasma cells within mucosal tissues revealed that they were preferentially located in the gills of rainbow trout. Analysis of gill mucosal secretions revealed that secIgD was the dominant antibody isotype, which contrasts the profile observed in serum. However, our data suggests that the number of IgD plasma cells in the gills of rainbow trout could not account for the elevated IgD concentration observed in the gill mucus. We hypothesize that serum IgD is preferentially transported across the gill epithelium to neutralize pathogens at this important site. The receptor responsible for trans-epithelial transport of IgD has proved elusive. However, the analogous distribution of IgD plasma cells and secreted IgD in the respiratory mucosa of trout and mammals would suggest that IgD provides an evolutionarily conserved function within this tissue.
Potential role of TSLP and IL-16 for migration and proliferation in Mycosis Fungoides T cells (161.15)
Authors: Tuzova Marina , Richmond Jillian , Wolpowitz Deon , Curiel-Levandrowsk Clara , Kupper Thomas , Cruikshank William 
Published: January 2023

Abstract
Mycosis Fungoides is a cutaneous T cell lymphoma disease characterized by CCR4+ T cells in skin plaques. While CCL22/CCR4 has been implicated, the mechanism for recruitment and expansion is not well understood. We have now identified elevated levels of IL-16 and thymic stromal lymphopoietin (TSLP) in the sera and skin of MF patients and investigated the potential role of these cytokines. Sera levels showed a stage-dependent increase of TSLP (3 fold versus control), and consistently, stage independent, elevated IL-16 levels. The source appears to be the skin, as both were positive compared with staining of normal skin. MF T cells expressed higher levels of TSLP receptor and expression correlated with CCR4 expression. In vitro migration studies indicated a 210% and 230% increase in migration to IL-16 and TSLP respectively. Pre-treatment of IL-16 prior to TSLP induced migration increased the migratory response to 280%, suggesting an additive effect. Addressing T cell proliferation, we determined that TSLP and IL-16 separately had minimal effects on proliferation however in combination proliferation increased 3 fold versus stimulated control T cells. Taken together our findings indicate the potential role of IL-16 and TSLP to recruit and expand MF T cells at sites of plaque formation in MF. Co-expression of TSLPR and CCR4 suggests a possible mechanism that at least in part would account for the prevalence of CCR4+ T cells in the skin of MF.
IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis (161.6)
Authors: Cui Yan , Kibe Ryoko , Zhang Shuzhong , Guo Darcy , Marrero Luis , Tsien Fern , Rodriguez Paulo , Zieske Arthur , Huang Jiaqiang , Li Wenqing , Durum Scott , Iwakuma Tomoo 
Published: January 2023

Abstract
IL-7 is essential for T cell survival and development. IL-7 receptor (IL-7Rα) efficiency manifests SCID due to substantial thymocyte apoptosis. We hypothesized that IL-7Rαnull-induced apoptosis is partially mediated by an elevated p53 activity. To investigate the genetic association of IL-7Rα signaling with the p53 pathway, we generated IL-7Rαnullp53null (DKO) mice. DKO mice exhibited a marked reduction of apoptosis in developing T cells and an augmented thymic lymphomagenesis with telomere erosions and exacerbated chromosomal anomalies, including chromosome duplications, breaks, and translocations. In particular, Robertsonian translocations, in which telocentric chromosomes fuse at the centromeric region, and a complete loss of telomeres at the fusion site occurred frequently in DKO thymic lymphomas. Cellular and molecular investigations revealed that IL-7/IL-7Rα signaling withdrawal diminished the protein synthesis of POT1 (protection of telomere 1), a subunit of telomere protective complex shelterin, leading to telomere erosion and the activation of the p53 pathway. Blockade of IL-7/IL-7Rα signaling in IL-7-dependent p53null cells reduced POT1 expression and caused telomere and chromosome abnormalities similar to those observed in DKO lymphomas. This study underscores a novel function of IL-7/IL-7Rα during T cell development in regulating telomere integrity via POT1 expression and provides new insights into cytokine-mediated survival signals and T cell lymphomagenesis.
Sinonasal epithelial cell derived IL-33 induces IL-13 in ST2+ innate lymphoid cells in chronic rhinosinusitis. (161.8)
Authors: Shaw Joanne , Fakhri Samer , Citardi Martin , Corry David , Kheradmand Farrah , Liu Yong-Jun , Luong Amber 
Published: January 2023

Abstract
Chronic rhinosinusitis (CRS) is an inflammatory process of the nasal and paranasal sinus mucosa that affects more than 40 million people annually. CRS without nasal polyps (CRSsNP) or with nasal polyps (CRSwNP) are associated with Th1 and Th2 cytokine polarization respectively. Although the pathophysiology of CRS remains unclear, recent studies have implicated a role for infectious agents including fungus, bacteria and bacterial superantigens in this chronic disease. Here we investigated the role of the epithelial cell derived cytokine IL-33 in the pathophysiology of CRS. Using quantitative real-time PCR we found elevated expression of the IL-33 receptor ST2 in inflamed sinonasal mucosa from CRSwNP patients compared to CRSsNP patients and healthy controls. Further, we found significant induction of IL-33 from epithelial cells derived from inflamed mucosa of CRSwNP patients as compared those derived from CRSsNP patients in response to stimulation with an extract of the filamentous fungus Aspergillus fumigatus. We discovered that IL-33 promotes the secretion of IL-13 from CD45+ cells isolated from inflamed mucosa of CRSwNP patients and subsequently discovered a unique population of ST2+ innate lymphoid cells responsible for the production of IL-13 in response to IL-33 stimulation. Collectively these data provide evidence for a role for sinonasal epithelial cell derived IL-33 and an IL-33 responsive innate lymphoid cell population in the pathophysiology of CRS.
Efficiency of colon cancer RNA-transfected DC vaccine is enhanced by previous treatment of tumor cells with low concentration of 5-fluorouracil (162.11)
Authors: Kaneno Ramon , Camargo Marcela , Gorgulho Carolina , Frederico Juliana , Ikoma Maura 
Published: January 2023

Abstract
We have recently observed that human DCs treated with low doses of antitumor chemotherapeutic agents became them more efficient to stimulate T lymphocytes, whereas treatment of tumor cells with low concentrations of drugs made them more immunogenic than wild type cells. In this study we aimed to evaluate whether transfection of DC with drug-treated tumor cells RNA, enhances the effectiveness of DC-based vaccine, and if modulatory effects of drugs can be observed in vivo. To achieve these goals, C57/Bl-6 mice were s.c inoculated with MC-38 cells and 10 days later they were treated with DC transfected with RNA from MC-38 cells pre-treated with the minimum effective concentration of 5-fluorouracil (5-FU). Vaccination with these DC decreased the tumor growth, being the tumor size 40% lower than the Control. DC phenotyping showed that transfection increased the percentage of CD86+ (55% higher than control), CD40+ (57% higher), and MHC class II+ cells (58% higher). Spleen cells of tumor-bearing mice were co-cultured with MC-38 target cells and the supernatants evaluated for IFN-γ. Vaccination with transfected-DC was able to increase the in vitro production of IFN, compared with control. Our results suggest that treatment of tumor cells with minimum effective concentration of 5-FU induces transcriptional changes that can be transfered to DC by RNA transfection, enhancing their ability to stimulate the antitumor response.
Spatiotemporal analysis of illegitimate V(D)J deletions in Notch1 and Bcl11b genes (162.14)
Authors: Champagne Devin , Shockett Penny 
Published: January 2023

Abstract
Aberrant V(D)J recombination events in oncogenes and tumor suppressor genes are implicated in development of T-cell leukemias and lymphomas. Previously, others identified hotspots for deletional DNA rearrangements adjacent to cryptic recombination signal sequences in Notch1 and Bcl11b genes in thymus of adult mice with radiation-induced thymic lymphomas. Interestingly, these rearrangements were also found at detectable frequencies in thymus of unirradiated WT animals suggesting that factors in addition to deletions contribute to development of lymphomas, but the frequency of deletions at different developmental stages or in peripheral lymphoid organs was not analyzed. To determine the timing, frequency, and tissue distribution of Notch1 and Bcl11b deletions during development, we are examining tissues harvested at different developmental stages from C57BL/6 mice. We detect these deletions in thymus at all ages examined from fetus to 6 months. Deletions are also detected in spleen, consistent with the presence of T cells bearing deletions in the circulating lymphocyte pool. We are analyzing sequences of deletion junctions for clonal relationships in individual animals and performing broken DNA end analysis for ongoing deletions. We are also using an inducible tetracycline-regulated RAG transgenic mouse system to determine if these rearrangements can occur at all ages with induced RAG expression or are limited to specific developmental windows.
Modulation of immunostimulatory and inhibitory signals augments T cell function by distinct mechanisms in the ovarian cancer microenvironment (162.15)
Authors: Duraiswamy Jaikumar , Freeman Gordon , Coukos George 
Published: January 2023

Abstract
Infiltrating T cells (TILs) with anti-tumor potential exist in patients with ovarian cancer. However, tumor microenvironment mediates induction of immunosuppressive molecules, such as PD-1 and CTLA4, on ovarian TILs. We assessed the interaction between PD1:PD-L1, PD-1:PD-L2, PD-L1:B7.1 and CTLA4:B7.1 pathways and their relative contribution in modulating TIL function. First, we evaluated the functional impact of PD-1 and CTLA4 on antigen-specific TILs in vitro from ovarian cancer patients. For in vivo studies, we used two mouse models: i) ID-8, a syngeneic model of ovarian cancer, and ii) a humanized model (HLA-A2+ NSG mice reconstituted with human CD34+ cells). PD-1 and CTLA4 blockade in ID-8 model resulted in partial tumor rejection. However, combining one or more of the following immune modulators, i) whole tumor vaccines expressing either GM-CSF or Flt3-ligand, ii) CpG-ODN, a TLR9 agonist, iii) anti-4-1BB agonistic antibody or iv) murine IL-15, added value to inhibitory blockade. In case of humanized mice, immune checkpoint blockade alone caused regression of human ovarian tumors. Our study shows that combining immunomodulators reject ovarian tumors by i) elevating T cell infiltration into tumors, ii) decreasing intratumoral regulatory T cell population and iii) increasing inflammatory cytokine production. We thank Drs. James P. Allison and Michael Curran (GM-CSF and Flt3L plasmids), Dr. Rafi Ahmed and Dr. John D. Altman (tetramers).
Cytomegalovirus-based vaccine induces protective immunity against melanoma (162.19)
Authors: Qiu Zhijuan , Maher Leigh , Adler Barbara , Khanna Kamal 
Published: January 2023

Abstract
Cytomegalovirus (CMV), which belongs to herpesviridae family, infects 40-60% of the population in developed country and more than 90% in developing country. It can establish life-long, asymptomatic infection in immunocompetent individual. CMV infection elicits strong adaptive immune responses, and superinfection is observed despite of the presence of CMV-specific immunity. Those unique characteristics make CMV a potentially promising vaccine vector. Here we used recombinant CMV that expresses ovalbumin (CMV-OVA) and examined its efficacy in protecting mice from OVA-expressing B16 melanoma (B16-OVA). We showed that in both therapeutic and prophylactic settings CMV-OVA vaccination significantly reduced tumor burden in mice in an antigen-dependent manner. We further designed CMV-based vectors that express the B16 endogenous antigen gp100 (CMV-gp100) and a mutant (CMV-gp100KGP), and evaluated their ability to protect mice against highly metastatic lung B16-F10 melanoma. Our results demonstrated that both CMV-gp100 and CMV-gp100KGP provided strong protection against B16-F10 melanoma. However, CMV-gp100KGP, which elicited an antigen specific CD8 T cell response against the self-protein gp100, provided better protection when compared to the CMV-gp100 that failed to generate gp100-specific effector CD8+ T cells. In conclusion, our studies demonstrated the efficacy of CMV-based vaccines to prevent and treat tumors.
CD40L expression by CD8+ T cells is essential for successful rejection of SV40 T antigen expressing tumor cells in the absence of CD4+ T cells (162.38)
Authors: Stark Regina , Frentsch Marco , Listopad Joanna , Schulz Axel , Meier Sarah , Blankenstein Thomas , Thiel Andreas 
Published: January 2023

Abstract
Cytotoxicity is considered to be the main effector function of CD8+ T cells in the immune system. However, we demonstrate here that CD40L, one of the central effector molecules of CD4+ helper T cells, is expressed by a substantial part of human and murine CD8+ T cells after activation. Human central as well as effector memory CD8+ T cells comprise up to 50% CD40L+ cells after polyclonal activation. These CD40L+ CD8+ T cells display a non-cytotoxic phenotype and resemble functionally various distinct CD4+ T helper cell subtypes with respect to expression of IL2 and IFNγ or IL4 as well as with respect to their potential to induce activation of B cells and maturation of DCs in vitro. To investigate the functional relevance of CD40L expression by CD8+ T cells we analyzed a murine anti-tumor response. During the whole course of the response 50% of the tumor-specific CD8+ T cells expressed CD40L. While application of CD40L competent wt CD8+ T cells to Rag1ko mice challenged with the tumor cells prevented the establishment of solid tumors, injection of CD40Lko CD8+ T cells resulted in a non-controlled tumor progression similar to non-treated tumors. Our results disclose an essential functional relevance of CD40L expressed by CD8+ T cells. Particularly in situations where CD4+ T-cell help is diminished, MHC-II antigen presentation is reduced or limited danger signals are present, CD40L+ CD8+ T cells may exert essential helper responsibilities for a competent cellular immune response.
Increased Th17 cells in the tumor microenvironment is mediated by tumor-secreted PGE2 (162.42)
Authors: Liu Jianguo , Ning Huan , Qian Xuesong 
Published: January 2023

Abstract
Tumor microenvironment can convert the host immune responses to favor tumor growth. However, the underlying mechanisms of how tumor cells educate host immunity are still largely unknown. We found that Th17 cells were increased in the peripheral blood, spleen and tumor tissues of mammary gland tumor-bearing mice. Th17 cell survival factor, IL-23 was overexpressed in tumor tissues isolated from both mouse and human breast cancer patients. Soluble molecules secreted from tumor cells but not normal breast epithelial cells induced IL-23 protein secretion in DCs via induction of the p19 mRNA expression. Our data further indicates that tumor-secreted PGE2 via its receptor EP2 and EP4 enhanced IL-23 p19 gene transcription through binding to the cAMP-response element in the p19 promoter. Blocking PGE2 synthesis by NS398, a Cox2 inhibitor, abrogated the enhancement of p19 expression both in vitro and in vivo. Furthermore, blocking PKA by H89 completely abrogated the inductive effects of tumor conditioned medium and PGE2 on p19 transcription. In line with this finding, cAMP active analog, Forskolin mimics the PGE2 effect. Taken together, our results indicate that tumor-secreted PGE2 differentially induce IL-23 but not IL-12 production in the tumor microenvironment which could promote Th17 cell expansion. This inductive effect is mediated through cAMP/PKA signaling transduction pathway by increasing p19 transcription.
TLR5 mediated regulation of tumor growth in an inducible model of cancer (162.48)
Authors: Rutkowski Melanie , Escovar-Fadul Ximena , Sarmin Fahmida , Stephen Tom , Allegrezza Michael , Gil-Guerva Oswaldo , Tesone Amelia , Conejo-Garcia Jose 
Published: January 2023

Abstract
It has been reported that up to 25% of the human population carries a dominant point mutation in TLR5 resulting in the loss of TLR5 signaling. TLR5 expression is paramount in modulating the balance of regulatory FoxP3+ and proinflamatory IL-17+ T cell lineages, two cellular subsets with potentially divergent roles in cancer. However, in the context of cancer, the significance of this mutation remains unknown. Sequencing of cDNA isolated from human ovarian tumor specimens revealed that 6% of tumor specimens harbor a functional mutation in TLR5, suggesting that a loss in TLR5 signaling results in “resistance” to cancer. To further investigate the role of TLR5 signaling in cancer progression, we utilized a novel p53 and KRas dependent model of inducible cancer. TLR5-/- mice had a remarkable delay in tumor onset and a dramatic reduction in tumor burden. Corresponding to the delayed tumor onset, we observed that T cells sorted from the tumor draining lymph nodes of TLR5-/- mice were able to vigorously recall against tumor antigens compared to a profound paralysis of effector function in T cells sorted from the draining lymph nodes of WT mice. These data indicate for the first time that pattern recognition receptors may influence the elimination and/or equilibrium phases of tumor progression at extraintestional locations, pinpointing potentially novel pathways to target for immunotherapy.
Serum amyloid A3 mediates inflammation-related tumor growth by fortifying the immunosuppressive mechanism of myeloid-derived suppressor cells (162.7)
Authors: Lee Jung-Mi , Chae Min-Ji , Park Young-Jun , Kim Yun-Sun , Kim Eun-Kyung , Kang Chang-Yuil 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs), which suppress diverse innate and adaptive immunity and thereby provide a tumor evasion mechanism, are emerging as a key population linking inflammation to cancer. Although many inflammatory factors inducing MDSCs have been known, the crucial components and the underline mechanisms remain elusive. In this study, we demonstrated for the first time a novel mechanism of serum amyloid A (SAA) 3, a well-known inflammatory marker, connecting inflammation and MDSCs. We found that tumor progression or hSAA treatment specifically acted on Mo MDSCs in subsets of MDSCs to induce SAA3 expression. These resulted in enhancing the survival and suppressive function while inhibiting the GM-CSF-induced differentiation of Mo MDSCs to activated macrophages through TLR2 signaling. Therefore, it suggests a novel mechanism that inflammation exacerbates cancer progression with the mediation of Mo MDSCs through SAA3. This study also provides new insight into increasing immunosuppressive activity of Mo MDSCs with tumor growth, demonstrating that SAA3 is specifically increased in Mo MDSCs as tumor grows.
B7-CD28 costimulation blockade via CD28Ig differentially modulates helper T cell differentiation without affecting Tregs (163.1)
Authors: Cho Hyoung-Soo , Kim Yong-Hee , Park Chan-Sik , Iwakura Yoichiro , Kim Sang-Joon , Park Chung-Gyu 
Published: January 2023

Abstract
B7-CD28 costimulation plays a prominent role in T cell full activation, and its blockade renders T cell anergic. CTLA-4Ig has been known to bind B7 ligands and effectively suppress T cell responses. However, CTLA-4Ig has been also reported to have a negative effect on Tregs. In the present study, we used CD28Ig to inhibit B7-CD28 engagement while sparing Tregs. CD28Ig dose-dependently suppressed alloreactive T cell proliferation, and it did not exert any harmful effect on the cellularity, frequency, and suppressive function of Tregs in mice. Next, we applied CD28Ig in mouse islet allograft model, and graft survival was significantly prolonged upon treatment in comparison to untreated control without negatively affecting Tregs. Interestingly, CD28Ig effectively controlled Th1 response in treated recipients while concomitantly upregulated both Th17 and Th2 response. Also, we further confirmed that Th17 is responsible for an eventual allograft rejection. CD28Ig differentially affected helper T cell differentiation by modulating lineage-specific transcription factor expression. Moreover, both expression of p-STAT3 and 6 were increased in response to CD28Ig, but Th1-associated p-STAT1 and 4 expression was repressed. Altogether, we here demonstrate that B7-CD28 blockade via CD28Ig differentially modulates helper T cell differentiation without dampening Treg integrity, and this implicates a new therapeutic strategy for regulating T cell response in autoimmunity or transplantation.