bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Mycobacterium tuberculosis-specific CD4 T cell immune repertoire in rhesus macaques overlaps with human responses (MPF2P.752)
Authors: Lindestam Arlehamn Cecilia , Mothe Bianca , Dow Courtney , Dillon Myles , Wiseman Roger , Bohn Patrick , Karl Julie , Golden Nadia , Foreman Taylor , Mehra Smriti , Scriba Thomas , Kaushal Deepak , O'Connor David , Sette Alessandro 
Published: January 2023

Abstract
Animal models to study the process of TB pathogenesis and vaccine development are of importance. NHP models, especially Rhesus macaques, are attractive because of available resources to evaluate their immunogenetic backgrounds and the aerosol model closely mimics the human infection route. In this study, we characterized the MHC immunogenetic background of a cohort of animals that have been vaccinated and/or infected with Mtb, defining 54 new immunodominant CD4 T cell epitopes using IFNγ ELISPOTs with antigens utilized in human clinical trials. Antigens which are immunodominant in humans are also immunodominant in rhesus macaques, including Rv3875 (ESAT-6) and Rv3874 (CFP10). Interestingly, the shared responses were not due to common ancestry or inbreeding upon identifying MHC alleles. Instead, the results indicate promiscuous binding, which is the first account of this phenomenon in the rhesus macaque TB model of infection. These results suggest that while the CD4 response of NHPs to TB is broad and heterogeneous, epitope sets can be defined to broadly follow and characterize these responses in genetically heterogeneous NHP animal cohorts. To our knowledge, this is the first comprehensive epitope identification effort for non-human primates. We reveal a profound repertoire overlap between epitopes recognized in NHPs and in humans. These findings have important implications for the evaluation of new vaccines and diagnostics in the setting of non-human primate model of TB.
Differential function of Ag-specific CD4 T cells from sepsis-induced lymphopenia is influenced by gut microbiota (MPF2P.744)
Authors: Griffith Thomas , Cabrera Javier , Babcock Jeffrey , Badovinac Vladimir 
Published: January 2023

Abstract
Sepsis changes the composition and functional potential of the naïve CD4 T cell repertoire, but the mechanism(s) that control such changes are unknown. We posited that the constituents of the gut flora play an important role in defining the responsiveness of CD4 T cell populations specific for Ag present in the commensal bacterial species that establish polymicrobial sepsis after cecal-ligation and puncture (CLP) versus those CD4 T cells undergoing sepsis-induced Ag-independent homeostatic proliferation. To test this hypothesis, we tracked the loss/recovery and function of CD4 T cells specific for an Ag present in segmented filamentous bacteria (SFB) in mice containing or devoid of this bacteria in their gut. SFB-specific CD4 T cells underwent Ag-driven proliferation in CLP-treated SFB+ mice, but not in SFB- mice. This correlated with their functional ability after secondary infection with SFB Ag-expressing Listeria. Interestingly, we found that a second CD4 T cell population specific for the influenza NP311 epitope underwent differential recovery and function depending on the mouse vendor, suggesting antigenic stimulation as a result of cross-reactivity with some yet-to-be defined epitope expressed by the gut commensal bacteria. Our data suggest the extent of recovery and function of a particular Ag-specific T cell population during sepsis can determined by the intestinal “health” of the individual, regardless of possible genetic similarities.
The trophic stage of the opportunistic fungal pathogen Pneumocystis murina suppresses β-1,3-glucan-induced cytokine production, but is sufficient for generating protective CD4+ T cell and B cell responses (MPF2P.746)
Authors: Evans Heather , Garvy Beth 
Published: January 2023

Abstract
Pneumocystis species are opportunistic fungal pathogens that cause severe pneumonia in immunocompromised hosts. The life cycle of Pneumocystis species consists of a trophic stage and ascus-like cysts. Our lab has published data demonstrating that cysts stimulate NF-κB translocation in alveolar macrophages, but the trophic form does not. Here, we demonstrate that bone marrow-derived dendritic cells pulsed with mixed P. murina express more IL-1β and induce greater CD4+ T cell interferon-γ production than bone marrow-derived dendritic cells pulsed with the trophic form alone. Additionally, our data indicate that the trophic form suppresses β-1,3-glucan-induced IL-1β production by bone marrow-derived dendritic cells. β-1,3-glucan is the predominant structural component in the cyst wall, but is not produced by the trophic form. Despite evidence of immunosuppression, our data demonstrate that the trophic form stimulates protective CD4+ T cell and B cell responses. CD4+ T cells transferred from BALB/c donor mice infected with the trophic form alone mediate clearance in RAG2KO host mice infected with either the trophic form or mixed P. murina. Infection with the trophic form generates protective B cell responses that mediate clearance following reinfection with either trophozoites or mixed P. murina. We propose that the trophic stage suppresses β-1,3-glucan-induced cytokine production, but is sufficient for stimulating protective responses in immunocompetent individuals.
Delayed viral clearance after respiratory tract infection results in prolonged inflammation in vitamin A deficient animals despite the presence of regulatory T cells (MUC1P.902)
Authors: Penkert Rhiannon , Surman Sherri , Sealy Robert , Jones Bart , Vogel Peter , Neale Geoff , Hurwitz Julia 
Published: January 2023

Abstract
Vitamin A deficiency (VAD) is a global health problem that persists in over half the countries in the world, affecting an estimated 250 million preschool children. VAD individuals suffer increased morbidity and mortality during enteric and respiratory infection, as vitamin A is an important regulator of immune system function. Previously, our lab has demonstrated that VAD mice have an impaired response to respiratory virus infection, exhibiting decreased IgA and CD8+ T cell responses to infection. Here we show that VAD mice fail to clear viral infection from the respiratory tract with the same efficiency as control vitamin A sufficient animals. We observed that prolonged viral presence can associate with an increased potential for T cell activation. As a result VAD animals experience a cytokine storm comprised of a mixed Th1/Th2 response including IFN-gamma, IL-4, IL-6 and IL-10 cytokines. Increased cytokine expression can be detected both on the transcriptional and protein level. Despite previous reports attributing VAD-related inflammation to a reduced frequency of regulatory T cells in the intestine, we observe no reduction in the number of FoxP3+ T cells in the respiratory tract of VAD animals compared to controls. Our results suggest that the increased inflammation observed during respiratory infection of VAD animals is due, at least in part, to poor IgA and CD8+ T cell responses and delayed viral clearance, and not exclusively to an absence of regulatory T cells.
Interleukin-10 is a critical regulator of white matter lesion containment following viral induced demyelination (MUC2P.940)
Authors: Puntambekar Shweta , Hinton David , Yin Xinghua , Savarin Carine , Bergmann Cornelia , Trapp Bruce , Stohlman Stephen 
Published: January 2023

Abstract
Formation of the astroglial scar in response to CNS injury is essential in limiting inflammation and damage to defined areas and initiating repair.The universal nature of this response suggests that defining mechanisms by which astrocytes segregate areas of tissue injury and promote repair is fundamental to confining demyelination.Neurotropic coronavirus induces an acute encephalomyelitis along with focal demyelination in which the initial lesions only increase slightly after the control of infection.Focal lesions are characterized by axonal sparing, myelin ingestion by microglia,and glial scars associated with hypertrophic astrocytes.Virus control is accelerated in mice lacking anti-inflammatory IL-10 resulting in limited initial demyelination.Despite ongoing viral control lesions fail to be confined and show sustained expansion providing a model of dysregulated white matter injury temporally remote from the acute CNS insult.Expanding IL-10-/- lesions are characterized by sustained microglial activation, partial loss of deactivated microglia and a lack of galectin-1 expressing astrocytes.Although IL-10 deficiency does not prevent astrocyte hypertrophy, astrocyte organization into mesh like structures at lesion borders is impaired. Formation of discrete foci of demyelination correlated with IL-10Rα expression on astrocytes in lesioned areas, highlighting a critical role for IL-10 signaling to astrocytes in limiting the expansion of the initial lesions into adjacent areas.
Human decidual CD8+ effector T cell responses in pregnancy (MUC2P.924)
Authors: van der Zwan Anita , Strominger Jack , Tilburgs Tamara 
Published: January 2023

Abstract
A unique challenge for maternal immune cells during pregnancy is to tolerate an allogeneic fetus, and yet to remain competent to respond to invading pathogens. CD8+ effector T cells play a key role in protection against virus infections and may directly recognize fetal MHC alloantigens expressed on invading fetal extravillous trophoblasts (EVT). HLA-C is the only polymorphic MHC molecule expressed by EVT and a potential ligand for the TCR of decidual CD8+ T cells (CD8+ dT). The number of differentiated, effector-memory (EM) CD8+ dT at the fetal-maternal interface was increased at least two-fold, while naïve CD8+ dT were nearly absent. These EM CD8+ dT had reduced expression of the cytotoxic molecule perforin when compared to peripheral blood EM CD8+ T cells (CD8+ pT). However, upon stimulation with anti-CD3/28, CD8+ dT increased expression of perforin, granzyme B and secreted IFN-γ and TNFα. Thus, CD8+ dT are not anergic and are able to mount a cytolytic response. Furthermore, after co-culture with EVT for 3 days the degranulation potential of CD8+ dT and their secretion of TNFα were inhibited. Interestingly, degranulation was inhibited only when CD8+ dT and EVT were obtained from the same pregnancy, not when EVT and CD8+ dT came from unmatched samples. These data may suggest that EVT inhibit CD8+ dT in an antigen-specific manner. Antigen specificity of CD8+ dT and factors that prevent a cytolytic CD8+ dT response to allogeneic fetal EVT are key topics for future research.
Memory B cells with gut-homing potential are generated by a prototype anti-enterotoxigenic E. coli vaccine given by intradermal immunization with LT(R192G) as an adjuvant (MUC3P.945)
Authors: Laird Renee , Shahabudin Sakina , Clarkson Kristen , Kaminski Robert , Savarino Stephen , Riddle Mark , Gutierrez Ramiro , Maciel Milton 
Published: January 2023

Abstract
Lymphocytes that express α4β7 integrin can home to the gut mucosa through interactions with MAdCAM-1 addressin on the intestinal endothelium. α4β7+ Ag-specific plasmocytes and memory B (BM) cells can be found after infection or experimental challenge with enteric pathogens as well as mucosal immunization, yet gut-homing B cells have not been reported in high frequencies in humans after parenteral immunization. Intradermal (ID) immunization is an attractive delivery route for enteric vaccines due to a potential connection between the skin and gut. Mucosal responses may be further enhanced by the addition of adjuvants such as LT(R192G), an attenuated form of the enterotoxigenic E. coli (ETEC) LT toxin. We analyzed BM cell generation in volunteers with two prototype vaccines based on the ETEC class 5a fimbriae tip adhesin CfaE with LT(R192G) by ID delivery. We observed both anti-CfaE and -LTB IgG and IgA BM cells, with a higher prevalence of Ag-specific IgG BM cells. Interestingly, anti-LTB IgA and anti-CfaE IgG BM cells were elicited at frequencies similar to those reported after ETEC infection, whereas anti-LTB IgG BM cells were found in higher frequencies after ID immunization compared to infection. The frequencies of anti-CfaE and -LTB IgG BM cells were similar in α4β7+ and α4β7- fractions, while the majority of anti-CfaE and -LTB IgA BM cells were α4β7-. These data suggest that the adjuvant LT(R192G) may be used to enhance mucosal BM responses following ID immunization.
Modeling mucosal immunity- gut microbiota interactions during Clostridium difficile infection (MUC3P.948)
Authors: Viladomiu Monica , Leber Andrew , Hontecillas Raquel , Abedi Vida , Hoops Stefan , Bassaganya-Riera Josep 
Published: January 2023

Abstract
Clostridium difficile is a facultative pathogen associated with antibiotic-induced infections which result in an exuberant inflammatory response, leading to nosocomial diarrhea, colitis and even death. We have previously reported novel evidence supporting a role of T cells in modulating host responses to C. difficile. Specifically, T cell alteration towards a pro-inflammatory phenotype due to lack of PPARγ resulted in increased disease symptoms and colonic pathology, which correlated with the abrogation of T cell regulatory (Treg) responses and shift towards a Th17-driven cellular response. To better understand the role of T cells during C. difficile infection from initiation through expansion to resolution, we built a computational model of the cellular host response to the bacterium. In line with our experimental findings, the model demonstrates a crucial role of Th17 effector and Treg responses, as well as an important contribution from commensal bacteria populations in the clearance of C. difficile and colonic pathology. Simulation results predict that proper clearance of infection with reduced damage to the epithelium is possible through a shift in the relative populations of Th17 and Treg cell subsets or through an accelerated regrowth of beneficial commensal strains. Our modeling provides novel insights on the mechanisms regulating C. difficile-associated immunopathology and show the path towards safer and more effective therapeutic interventions.
Targeted complement inhibition improves recovery in murine spinal cord injury model (THER2P.956)
Authors: Narang Aarti , Qiao Fei , Atkinson Carl , Kulik Liudmila , Holers V. , Yang Xiaofeng , Tomlinson Stephen 
Published: January 2023

Abstract
Spinal cord injury (SCI) initiates a cascade of events including ischemia, excitotoxicity and inflammation. Tissue injury exposes neoepitopes that elicit an innate immune response following their recognition by natural IgM. To investigate the role of natural IgMs in propagating SCI, we identified two IgM mAbs that bind to post-ischemic cell membranes.These mAbs B4 and C2 recognize annexin IV and a subset of phospholipids, respectively. Compared to wt mice, Rag1-/- mice recovered significantly better post SCI. However, reconstitution of Rag1-/- mice with B4 or C2 mAb restored injury to levels seen in wt animals. Further, we used peritoneal cavity hypotonic shock procedure to deplete B1a B cells (source of natural IgM), while keeping other components of the immune system intact.This resulted in reduced IgM and complement (C) deposition and protection from injury, indicating SCI is driven by the binding of specific natural IgM clones. Based on these data, we investigated a strategy to target a C inhibitor to the injured spinal cord. We constructed a single chain derived from B4IgM (B4scFv) and linked it to Crry, an inhibitor of C3 activation. This construct significantly improved locomotor recovery following SCI by both competing with pathogenic IgMs and inhibiting C. This study identifies pathophysiologically important epitopes expressed within the spinal cord after contusion injury, and describes a novel strategy for targeted C inhibition to reduce secondary injury after SCI.
JAK2 inhibition prevents NK-released IFNγ-mediated PD-L1 upregulation and enhances cetuximab mediated ADCC of HNC cells (TUM2P.1014)
Authors: Concha-Benavente Fernando , Ferris Robert 
Published: January 2023

Abstract
Programmed death ligand 1 (PD-L1) is an immunosuppressive molecule expressed by many cancer types, including a large proportion of head and neck cancers (HNC), and ligation of its receptor, programmed death 1 (PD-1), induces exhaustion of effector T cells, however its expression level and function on natural killer (NK) cells is not well characterized yet. It has been shown that interferon gamma (IFNγ) induces PD-L1 expression in many cancer types including glioblastoma, melanoma, lung and head and neck cancer (HNC). IFNγ signals through Janus Kinase 1/2 (JAK1/2) heterodimer complex and mediates signal transducer and activator of transcription 1 (STAT1) phosphorylation. Herein we demonstrate that IFNγ-mediated tumor cell PD-L1 expression is JAK2/STAT1 but not JAK1 dependent. Interestingly, NK cell activation through CD16 ligation of cetuximab coated tumor targets increased IFNγ release and PD-1 expression on NK cells. Therefore, blocking PD-L1/PD-1 axis is crucial in order to increase NK mediated antibody dependent cell cytotoxicity (ADCC). Herein, we demonstrate that specific JAK2 inhibition downregulated NK cell-derived IFNγ induced PD-L1 expression in tumor targets and enhanced cetuximab mediated ADCC. Our data suggest a crucial role for JAK2 in IFNγ mediated tumor cell PD-L1 upregulation. Importantly, JAK2 inhibition provides a logical strategy to increase tumor cell lysis through suppressing tumor cell PD-L1 expression in combination with anti-EGFR cetuximab therapy.
SLAMF6 signaling in murine chronic lymphocytic leukemia cells (TUM2P.1019)
Authors: Yigit Burcu , Chen Shihshih , Halibozek Peter , Arnason Jon , Chiorazzi Nicholas , Terhorst Cornelis 
Published: January 2023

Abstract
Chronic lymphocytic leukemia (CLL) is a circulating B cell tumor that initiates in the bone marrow and blood and spreads to the lymph nodes, liver and spleen. Disease pathogenesis is largely characterized by hyper-activation of B cell receptor (BCR) signaling and subsequent tumor accumulation in the secondary lymphoid organs. Targeting BCR downstream pathways with small inhibitor molecules, e.g. ibrutinib (an irreversible BTK inhibitor), shows great efficacy in the clinic. However, there is still a need for additional therapeutic targets for CLL, as patients eventually relapse. Because the homophilic cell surface receptor Slamf6 is highly expressed on CLL cells and plays a role in TFH - B cell interactions, the effects of anti-Slamf6 on the murine CLL cell line TCL1-192 was assessed. To this end SCID mice that had been transplanted with TCL1-192 received injections of mouse anti-Slamf6 (13G3) monoclonal antibody or isotype control. Injection of anti-Slamf6 significantly reduced tumor burden in the blood and spleen. This response is due to ADCC as well as to Slamf6 signaling as injections of F(ab’)2 fragments of anti-Slamf6 antibody results in down-regulation of proximal BCR components (pSyk, pBtk). Additionally, anti-Slamf6 resulted in a block in TCL1-192 tumor migration from the peritoneum to the blood and spleen. Overall, this study suggests that Slamf6 could be a potential new target for CLL therapy.
Identifying mechanisms of acquired resistance to immunotherapy (TUM2P.1025)
Authors: Jaiswal Ashvin , Ager Casey , Ai Midan , Bartkowiak Todd , Budhani Pratha , Curran Michael 
Published: January 2023

Abstract
Immunotherapy has demonstrated a remarkable potential to cure established cancer, but many tumors either relapse or fail to respond. The molecular mechanisms which drive these tumor relapses remain unknown. We hypothesize that tumors evolve resistance under immunotherapeutic pressure mediated by changes in gene expression which can be selected and propagated through serial passage and then identified and targeted. We are comparing untreated B16 melanoma tumors to those expanding despite treating with combinations checkpoint blockade (CTLA-4, PD-1, and PD-L1), 4-1BB-agonist antibody, adoptive transfer of TRP-1 specific CD4 T-cells, or growth in MHC-mismatched hosts. Through multiple in vivo passages, we have already selected a B16 melanoma tumor line that has evolved almost 100% resistance to combination blockade of CTLA-4, PD-1, and PD-L1, which could cure nearly 90% of tumor-bearing mice in the first cycle. After each passage under selective pressure of combination blockade, we have observed visible signs of increased angiogenesis correlating with enhanced therapy resistance. By determining the pathways engaged by these tumors to develop resistance to tumor-specific immunity, we hope to discover novel characteristics of the mammalian immune system as well as reveal new targets for immunotherapeutic intervention in melanoma patients.
Combination of anti-CD73 and agonistic anti-CD137 antibody therapy leads to tumor regression (TUM2P.1030)
Authors: chen siqi , Zhang Bin 
Published: January 2023

Abstract
Agonist antibodies (Ab) directed against costimulatory molecule CD137 (4-1BB) on the surface of antigen-primed T-lymphocytes are currently in various stages of pre-clinical and clinical development, though therapeutic benefit has been limited as single agents. Here, we examined the inhibitory role of CD73 on the antitumor efficacy of agonistic anti-CD137 Ab therapy. CD73-deificient mice treated with anti-CD137 Ab completely rejected CD73-nonexpressing B16-SIY melanoma growth when compared with wild-type mice, highlighting the importance of an inhibitory role for host-derived CD73. To explore the therapeutic relevance of these observations, we combined anti-CD137 and anti-CD73 Ab to treat mice with established B16-SIY melanoma. This combination therapy induced tumor regression associated with enhanced antitumor CD8+ T cell responses and reduced CD4+Foxp3+ regulatory T cells number and function. In contrast, neither anti-41BB nor anti-CD73 monotherapy is effective to control the growth of established melanoma. Our study demonstrates that CD73 blockade has critical implications for effective clinical targeting of CD137 and possibly other costimulatory molecules.
Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response (TUM2P.1006)
Authors: Moins-Teisserenc Helene , Felix Joana , Porcher Raphael , Pages Cecile , Sidina Irina , Cordeiro Debora , Maki Guitta , Viguier Manuelle , Maubec Eve , Toubert Antoine , Lebbe Celeste 
Published: January 2023

Abstract
CTLA-4 is the main negative regulator of T cell mediated antitumor immune responses. Treatment with Ipilimumab, a humanized anti-CTLA-4 mAb, was shown to provide increased survival in patients with melanoma. However, only a subset of patients benefit and it is therefore important to identify prognostic immunological correlates of clinical endpoints. 77 patients with stage III or IV melanoma were treated with ipilimumab every 3 weeks, during 9 weeks. Blood samples were collected at week 0, 3, 6, 9, 12. The clinical response was assessed at week 16. Lymphocyte phenotyping was performed on fresh blood samples. The median follow-up was 28 months with a median survival of 7 months, which was significantly improved when the absolute lymphocyte count (ALC) at the baseline was above 1000/uL. In addition ALC was predictive of disease control (DC) at week 16. Ipilimumab had a global effect on central, transitional and effector memory T cell subsets, with a marked increase of these populations between week 0 and 3 in patients with DC. In addition, higher proportions of Eomes+, Ki67+ and Granzyme B+ T cells were observed. These changes were associated with a significant decrease in the proportion of stem cell memory T cells (TSCM). These results suggest that Ipilimumab is able to reshape the memory subset at early time points and provide new insights into the mechanisms of memory T cell subset expansion with the potential involvement of TSCM.