bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic effect of HIV virion and bacterial LPS on memory B cell apoptosis (HUM8P.341)
Authors: Jiang Wei 
Published: January 2023

Abstract
Background: The effect of heightened microbial translocation on B cells in HIV infection is unknown. Methods: We examined the effects of HIV and LPS on CD27+IgD- memory B cell (mB) apoptosis in healthy controls. In vivo analysis was conducted on a cohort of 47 healthy and 49 HIV+ donors. Results: In vitro, exposure to LPS and HIV virus cooperated to induce mB death in PBMCs (P&lt; 0.05, n=21). The median percentage of annexin V binding mB was 22 (17.1-30.8) in medium, 23.5 (19.3-29.8) in HIV, 22.5 (16.5-28.8) in LPS, and 35.5 (26.8-44) in HIV plus LPS. This synergistic effect was abolished in pDC-depleted PBMCs (P&lt;0.05, n=5) or in the presence of neutralizing Ab against Fas or FasL (P&lt;0.05, n=7). HIV induced FasL in pDCs (P&gt;0.05, n=4). LPS and LPS plus HIV induced Fas on mB (P&lt;0.05, n=15) through mDCs. The induction of Fas was related to the susceptibility of mB to apoptosis by HIV and LPS (r=0.76, P=0.01). In vivo, in 46 HIV- and 56 HIV+ donors, mB apoptosis, Fas expression and plasma LPS were increased in HIV+ ART- and ART+ patients compared to controls (P&lt;0.05), but plasma FasL were similar in controls and patients (P=0.94). Correspondingly, a positive correlation was found between plasma FasL and HIV RNA (r=0.67, P&lt;0.0001), and the Fas on mB and plasma LPS (r=0.55, P&lt;0.0001) in HIV+ donors, but not in controls. Conclusion: This study suggests a novel mechanism of mB apoptosis mediated by LPS and HIV through the Fas/FasL pathway. DCs play an important role in this process.
Co-expression network analysis reveals immune response pathways important for pathogenesis of Chlamydial pelvic inflammatory disease (PID). (HUM8P.329)
Authors: Zheng Xiaojing , O'Connell Catherine , Nagarajan Uma , Wiesenfeld Harold , Hillier Sharon , Darville Toni 
Published: January 2023

Abstract
Processes driving development of immune pathology after Chlamydia trachomatis infection are poorly understood. To provide insight into the pathways that may be underappreciated by individual gene analysis, weighted gene co-expression network analysis was performed to identify network modules using blood transcriptional profiles of women with chlamydial PID (N=15) and asymptomatically infected women (N=84). Modules, defined as centrally connected genes, that were significantly associated with chlamydial PID were further accessed via Ingenuity Pathway analysis. Type I and type II interferon (IFN) signaling pathways were significantly up regulated in women with chlamydial PID. Up regulation of both of these pathways has been detected in the transcriptomes of patients with active tuberculosis, suggesting a parallel role in PID. Up regulation of aryl hydrocarbon receptor, agranulocyte/granulocyte adhesion and diapedesis pathways was also noted, while EIF2/EIF4, mTOR and ILK signaling, granzyme A/B signaling, cross talk between dendritic cells and natural killer cells, signaling in T helper cells and T cell receptor pathways were down-regulated. Pathways likely to contribute to immunopathogenesis, including migration of leukocytes and inflammation were activated in chlamydial PID, while those involved in cell growth/proliferation and clearance of infected cells were decreased. Bioinformatics provides a new avenue to improve understanding of chlamydial disease mechanisms.
Differential developmental requirement and peripheral regulation for dermal Vγ4 and Vγ6 IL-17-producing γδ T cells (IRC8P.479)
Authors: Cai Yihua , Fleming Christopher , Yan Jun 
Published: January 2023

Abstract
Dermal γδ T cells are professional IL-17-producing γδ T cells and play a critical role in skin inflammation. However, their development and peripheral regulation are still largely unknown. In this study, we demonstrated that dermal γδ T cells developed from fetal thymus and underwent homeostatic proliferation after birth with diversified TCR repertoire, mainly including Vγ4 and Vγ6. Thymus is absolutely required for dermal γδ T cell development. IL-17-producing Vγ6 T cells were bona fide resident in dermis and were reconstituted from fetal thymus while IL-17-producing Vγ4 dermal γδ T cells were mainly from bone marrow, suggesting precursors of dermal Vγ4 T cells may require extrathymic environment for maturation and gaining skin-homing property. In addition, we found that Vγ6 T cells were pathogenic to induce skin inflammation. Mice reconstituted with Vγ6 developed psoriasis-like skin inflammation upon IMQ application whereas Vγ4 T cells were preferentially expanded and the major IL-17 producer in IMQ-treated naïve mice. Although IL-23 and IL-1β were capable of driving dermal Vγ4 and Vγ6 T cell proliferation, IL-17 production was mainly from Vγ4 and IL-1 signaling was essential. These studies reveal a differential developmental requirement and peripheral regulation for IL-17-producing dermal Vγ6 and Vγ4 T cells. This work is supported by a grant from the National Psoriasis Foundation.
Repeated antigen exposure reverses endogenous CD8 T cell tolerance and is potentiated by IL-4 (MUC8P.804)
Authors: Thompson Emily , Nelson Christine , Vezys Vaiva 
Published: January 2023

Abstract
Elucidating the induction, maintenance, and reversal of self-tolerant CD8 T cells is imperative for understanding the development and progression of autoimmunity, as well as cancer. Using a mouse model that permits examination of responses to small intestinal self-antigen, we can evaluate endogenous polyclonal self-specific T cells that have undergone tolerance induction. This established CD8 T cell tolerance can be reversed after repeated antigen delivery, generating large numbers of activated, functional endogenous self-specific T cells. Interestingly, this response is reduced in IL-4 limiting conditions suggesting a mechanistic role for IL-4 in self-reactive CD8 T cells responses. We hypothesize that IL-4 is required for self-specific CD8 T cell selection, survival and/or responses to cognate antigen. We show that while IL-4 does not act directly on CD8 T cells, it does impact their proliferation, especially during Ag recognition. Interestingly, we can detect self-reactive T cells that have escaped thymic selection in unmanipulated mice, but these remain naïve, despite the presence of large amounts of cognate MHC:Ag complexes. Future studies will focus on elucidating the function and origin of IL-4 in self-specific responses and understanding properties of endogenous, polyclonal self-specific CD8 T cells in negatively selecting environments.
Inhibition of TWEAK signaling preserves the glomerular filtration barrier and ameliorates spontaneous murine lupus nephritis (THER6P.845)
Authors: Xia Yumin , Herlitz Leal , Gindea Simona , Wen Jing , Pawar Rahul , Misharin Alexander , Wu Lan , Wu Ping , Michaelson Jennifer , Burkly Linda , Putterman Chaim 
Published: January 2023

Abstract
The TNF superfamily member TWEAK acts through its receptor, Fn14, to mediate several key pathological processes known to be involved in lupus nephritis. To explore the potential for renal protection by targeting this pathway, we introduced the Fn14 null allele into the MRL/lpr lupus mouse strain. At 26 to 38 weeks of age, female MRL/lpr Fn14 knockout (KO) mice (backcross #8) had significantly lower levels of proteinuria, BUN, and creatinine as compared to Fn14 wild type (WT) mice. Furthermore, Fn14KO mice had significantly improved renal pathology, accompanied by attenuated glomerular and tubulointerstitial inflammation and less glomerular immune deposits. There were no detectable differences between the strains in either serum autoantibody levels or in splenic immune cell subsets, although less lymphadenopathy was observed in Fn14KO mice. Importantly, Fn14KO mice displayed substantial preservation of podocytes in kidney glomeruli. Moreover, we demonstrated that TWEAK signaling via Fn14 directly damaged the integrity of the glomerular filtration barrier through effects on both podocytes and glomerular endothelial cells. Inhibition of TWEAK signaling due to deficiency of the Fn14 receptor significantly improves renal disease in a spontaneous lupus nephritis model, likely through prevention of the direct injurious effects of TWEAK on the filtration barrier. Thus, blocking the TWEAK/Fn14 axis is a novel therapeutic target in immune-mediated proliferative glomerulonephritis.
Pharmacologic inhibition of RORγt regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo (THER6P.855)
Authors: Yang Jianfei , Skepner Jill , Ramesh Radha , Trocha Mark , Schmidt Darby , Baloglu Erkan , Lobera Mercedes , Carlson Thaddeus , Hill Jonathan , Miller Lias , Barnes Ashley , Boudjelal Mohamed , Sundrud Mark , Ghosh Shomir 
Published: January 2023

Abstract
IL-17-producing Th17 cells, Tc17 cells and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. Here we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated Th17-signature gene expression. In addition, TMP778 but not TMP776 inhibited IL-17 production in both human and mouse γδ T cells. IL-23-induced IL-17 production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, we are the first to demonstrate that RORγt inverse agonists (1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8+ Tc17 cells; (2) block imiquimod-induced cutaneous inflammation; (3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and (4) block IL-23-induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders.
IL-15 mediates alloreactive CD8 memory T cell resistance to CTLA4-Ig blockade. (TRAN3P.891)
Authors: Gorbachev Anton , Traitanon Opas , Baldwin William , Poggio Emilio , Fairchild Robert 
Published: January 2023

Abstract
Objective: The increased presence of alloreactive memory CD8 T cells in the peripheral blood of transplant patients is a risk factor for acute graft rejection and resistance to CTLA4-Ig immunosuppression. The mechanisms mediating this resistance are poorly understood. These studies tested the ability of IL-15, a cytokine produced in grafts during post-surgical inflammation, to confer memory CD8 T cell resistance to CTLA-4Ig blockade. Results: Addition of IL-15, but not IL-2 or IL-7, to co-cultures of purified CD28- or CD28+ memory CD8 T cells and allogeneic B cells induced proliferation of the CD28- memory cells. Proliferating CD28- memory CD8 T cells produced high amounts of IFN-g and TNF-a and up-regulated the cytolytic marker CD107a. IL-15 also induced rapid release of perforin and granzyme B by alloantigen-stimulated CD28- or CD28+ memory CD8 T cells. While CTLA4-Ig inhibited alloantigen-induced proliferation of CD28+ memory CD8 T cells, addition of IL-15 rescued this proliferation. CD28+CD8 memory T cells rendered resistant to CTLA4-Ig blockade by IL-15 down-regulated CD28, suggesting the loss of CD28 expression as one mechanism of resistance. Conclusions: IL-15 activates CD28- memory CD8 T cell to proliferate and to express effector functions in response to alloantigen and provokes down-regulation of CD28 on CD28+ memory CD8 T cells conferring resistance of these T cells to CTLA4-Ig mediated costimulation blockade.
Do farnesyltransferase inhibitors modulate immune responses by blocking cytokine secretion from alloreactive T cells? (TRAN3P.899)
Authors: Field Kenneth , Hayes Michael , James McMichael , Dieck Chelsea , Gaylo Alison , Crosby Erika 
Published: January 2023

Abstract
Farnesyltransferase inhibitors (FTIs) have been shown to modulate alloreactive immune responses in mouse models of transplantation (A.E. Gaylo, et al., Transplant Immunology 20 (2009) 163-170) and graft versus host disease (A.-K. Hechinger, et al. Haematoligica 98 (2013) 31-40). We are testing the hypothesis that FTIs modulate immune responses by blocking cytokine secretion from alloreactive T cells. By blocking T cell cytokine secretion FTIs could affect the differentiation of activated CD4+ T cells into Th1, Th2, or other effector subtypes. We have examined the ability of FTIs to affect cytokine secretion from various T cell subsets and T cell polarization in mice during an allorejection response. Using qPCR we quantified cytokine gene expression in graft-draining lymph nodes (GDLNs) isolated from mice during the rejection of an MHC class II-mismatched skin allograft (bm12 donors to B6 recipients). Using ELISpot assays, we also measured the number of alloreactive Th1 (IFN-γ producing) and Th2 (IL-4-producing) cells in GDLNs. In vitro T cell polarization of polyclonally-stimulated CD4+ T cells isolated from spleen was measured using IFN-γ, IL-4, IL-17, and FoxP3 intracellular staining. Using these various approaches, we found that FTI treatment differentially affects cytokine secretion from the CD4+ T cell subsets studied. These effects lead to differences in Th1/Th2 cell polarization that could explain the immunomodulatory activity of FTIs.
Small molecule agonists of CD11b/CD18 reduce leukocyte activation and recruitment to promote kidney allograft survival (TRAN3P.909)
Authors: Khan Samia , Faridi Mohd , Guo Lingling , George James , Agarwal Anupam , Gupta Vineet 
Published: January 2023

Abstract
Allograft rejection in kidney transplantation is associated with leukocyte infiltration, including myeloid cells expressing β2 integrin CD11b/CD18. We reported that activation of CD11b/CD18 by a small molecule compound, leukadherin-1 (LA1), increases leukocyte cell adhesion to the inflamed endothelium, prevents transmigration and inhibits leukocyte tissue recruitment resulting in improved kidney function in a murine nephritis model. Here we test whether LA1 mediated activation of CD11b/CD18 enhances kidney allograft survival in a mouse model of fully MHC-mismatched orthotopic kidney transplant, where C57BL/6J (H-2b) recipients received a kidney allograft from Balb/c mice (H-2d). Control recipients were treated daily with cyclosporine (CsA) for 2 weeks, while the test group received standard CsA therapy and daily LA1 injections during week 1 and alternate days during weeks 2-8. Renal allograft rejection was considered when mice displayed signs of ill health and high serum creatinine levels. Combination therapy reduced leukocyte infiltration and neointimal hyperplasia and increased graft survival from 48.5% (CsA only) to 100% (CsA and LA1) on day 60. At week 5, CsA treated controls had serum creatinine values of 0.6 mg/dl while LA1 and CsA treated mice had baseline values of 0.2 mg/dl. These findings indicate a crucial role for CD11b/CD18 in the control of leukocyte migration to the transplanted kidney and identify leukadherins as therapeutic agents for renal transplantation.
TIGIT inhibits CD8+ T cell effector function during chronic viral infection and cancer (TUM7P.933)
Authors: Grogan Jane , Johnston Robert , Comps-Agrar Laetitia , Hackney Jason , Yu Xin , Huseni Mahrukh , Yang Yagai , Eaton Dan , Park Summer 
Published: January 2023

Abstract
Tumors constitute highly suppressive microenvironments in which infiltrating T cells are functionally suppressed by co-inhibitory receptor ligands. We identify T cell Immunoglobulin and ITIM domain (TIGIT) as a co-inhibitory receptor that critically limits CD8+ T cell responses to cancer and chronic infection. Expression of TIGIT was highly correlated with T cell infiltration in a broad range of solid tumors, and both human and murine tumor-infiltrating lymphocytes coordinately expressed TIGIT and PD-1, a key marker of T cell exhaustion. In mouse models of chronic viral infection and cancer, antibody blockades of TIGIT and PD-L1 synergistically and selectively enhanced CD8+ T cell effector function, resulting in significant viral clearance and tumor rejection respectively. Anti-TIGIT mediated anti-tumor immune responses were durable, as treated mice possessed antigen-specific and CD8+ T cell-dependent protection against tumor re-challenge. Strikingly, these effects were dependent on the activity of TIGIT’s complementary co-stimulatory receptor, CD226, whose dimerization and function was impaired by direct interaction with TIGIT in cis; and ablation of TIGIT was sufficient to enhance CD226 co-stimulation in CD8+ T cells. These results reveal a novel mechanism of action for co-inhibitory receptors and define a critical role for TIGIT as a regulator of anti-tumor and other chronic CD8+ T cell responses in vivo.
Role of signal transducer and activator of transcription 6 in the development of colitis associated colorectal cancer (TUM7P.959)
Authors: Leon-Cabrera Sonia , Molina Emmanuel , Delgado Yael , Becerra Mireya , Ledesma-Soto Yadira , Gitierrez-Cirlos Emma , Rodriguez-Sosa Miriam , Avila-Moreno Federico , Chirino Yolanda , Perez-Plasencia Carlos , Terrazas Luis I. 
Published: January 2023

Abstract
STAT6 signaling pathway has important pathophysiologic implications in a variety of cell types and diseases. On cancer studies, mice lacking STAT6 display enhanced tumor immunity to both primary and metastatic mammary carcinomas. In humans, STAT6 protein has been found to be constitutively activated in several cancer types. However, the role of STAT6 in influencing the resistance or susceptibility of colon cancer cells to apoptosis and invasiveness/metastasis has not yet been validated during in vivo colitis-associated colon cancer (CAC).This study aims to identify the effects of STAT6 in tumorigenesis utilizing STAT6-KO mice in an experimental CAC model and evaluating changes in immune cell populations in the absence of this gene. CAC was induced in both STAT6-KO and WT mice by injection of 12.5 mg/kg AOM followed by three rounds of 2% DSS exposure to elicit colitis. On day 63 after CAC induction, mice were sacrificed. Colonic inflammation, proliferation and tumorigenesis were evaluated. Tumor numbers per mouse (0.8 versus 19.6; P=0.0001), and bowel weight (0.3 versus 0.6 g; P=0.05) were significantly decreased in STAT6-KO mice compared to WT mice. Furthermore, both inflammation and proliferation scores in colon from STAT6-KO mice were significantly lower than WT mice. Although additional studies are needed to clarify the mechanism(s) underlying improved anti-tumor immunity in STAT6-KO mice, these results may be a basis for an immunotherapy strategy in CAC development.
Cellular and molecular characterization of hagfish VLR-based adaptive immune system (VET2P.1043)
Authors: Li Jianxu , Guo Peng , Hirano Masayuki , Herrin Brantley , Cooper Max 
Published: January 2023

Abstract
Jawless vertebrates have an alternative adaptive immune system in which variable lymphocyte receptors (VLR) are somatically diversified through recombinatorial assembly of leucine-rich repeat cassettes during lymphocyte development. Three VLR loci (VLRA, VLRB, and VLRC) have been defined in lampreys and each is expressed by a distinct lymphocyte population. Lamprey VLRA and VLRC are expressed by T-like lineages of lymphocytes, whereas VLRB is expressed by a B-like lineage of lymphocytes, much like αβ T, γδ T and B cells in jawed vertebrates. Recently we have revised the nomenclature for the hagfish VLRs by defining a third VLR gene. Here, monoclonal and polyclonal antibodies were generated against invariant residues of hagfish VLRA, VLRB and VLRC and these were used to identify VLR-bearing lymphocytes and their products. We found that hagfish VLRA, VLRB and VLRC are expressed by three separate lymphocyte populations. Size-exclusion chromatography and western blot analysis indicated that multivalent VLRB proteins are released into the circulation, which suggests that hagfish VLRB+ cells are B-cell like. In contrast, neither VLRA nor VLRC was detectable in the plasma, supporting the hypothesis that these two lymphocyte populations are T-cell like. The demonstration of three lymphocyte populations in both lampreys and hagfish suggests that this tripartite lymphocytic differentiation program already existed in a common ancestor of the two cyclostome lineages around 480 Mya.
Leishmaniasis triggers changes in monocyte subsets in dogs. (VET2P.1048)
Authors: Goncalves Ricardo , Barbosa Vitor , Antonelli Lis , Mosser David , Tafuri Wagner 
Published: January 2023

Abstract
Peripheral blood monocytes are the largest group of circulating progenitor cells. Its functions have been revealed through the study of their subpopulations, especially in humans and mice in pathological processes. In Brazil, the parasite L. infantum is the cause of the canine visceral leishmaniasis. This study aimed to characterize subpopulations of peripheral blood monocytes from uninfected or L. infantum naturally infected dogs and compare their phenotypical and functional aspects. Blood samples were collected from uninfected and infected dogs, labeled by antibodies against different surface markers and analyzed by flow cytometry. It was observed two distinct populations according to CD14 expression: a population CD14High, constituting about 90% of the monocytes showing basophilic and horseshoe-shaped nucleus with greater phagocytic capacity, and another CD14Low, constituting about 10% of monocytes, showing less basophilic and kidney-shaped nucleus. The analysis of the other molecules showed different levels of expression between the two populations. In dogs with visceral leishmaniasis no difference in frequency was observed between populations, however there is an increase of CD14+ cells in infected dogs. We also noticed marked reduction of the expression of molecules related to the activation of monocytes, especially in the group of symptomatic dogs, indicating a possible inhibition on the capacity of these cells to control the disease.
Endogenously-processed influenza epitopes intersect with the classical MHCII presentation pathway via the GILT endosomal reductase (APP2P.104)
Authors: Veerappan Ganesan Asha Purnima , Miller Michael A , Eisenlohr Laurence C 
Published: January 2023

Abstract
CD4+ T cell activation is driven by recognition of pathogen-derived peptides (epitopes) displayed by MHC-II on the surface of antigen presenting cells. By convention, peptides derived from extracellular antigen are internalized and loaded onto MHC-II in the late endosome. However, our recent findings suggest that this is a minor contributor to influenza-derived peptide display. In order to elucidate alternative pathways, T cell hybridomas were developed to six different specificities derived from A/PR/8/34 influenza virus proteins. Fully half of the epitopes were found to be proteasome dependent, reflecting a major role for endogenous, cytosolic antigen processing. Intriguingly, endogenous processing of two epitopes, which are constrained within the neuraminidase protein (NA) by disulphide bonds, was strongly dependent on γ-interferon-inducible lysosomal thiol reductase (GILT), an enzyme that can be critical for exogenous processing. Presentation of these epitopes was also inhibited by primaquine (a compound that prevents trafficking from endosome to the plasma membrane) suggesting that the relevant GILT activity resides in the endosomal network. This interpretation was further supported by the observations that presentation of disulphide constrained synthetic peptides were also GILT dependent but responses to MHC-I restricted epitopes within NA are not. These results point to a novel alternative MHC-II pathway that includes both cytosolic and endosomal processing steps.