bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential serological immune imprinting following SARS-CoV-2 infection, vaccination, and breakthrough infection
Authors: Voss William , Huang Yimin , Marchioni Jeffrey , Seeger Allison , Paresi Chelsea , Kain Jessica , Townsend Douglas , Munt Jenny , Baric Ralph , Georgiou George , Lavinder Jason , Ippolito Gregory 
Published: January 2023

Abstract
Extensive efforts have been made to study the human immune response following SARS-CoV-2 infection. Recent work by our lab provided insights into the molecular-level composition of the circulating IgG antibody repertoire evoked by SARS-CoV-2 primary infection and revealed key properties of the spike-directed antibodies and the epitopes they target in convalescent plasma (Voss et al., Science 2021). We showed that the antibody response in mild SARS-CoV-2 infection is directed to epitopes outside the RBD and primarily to the S2 domain of the spike glycoprotein.
The continual emergence of globally circulating SARS-CoV-2 variants underscores the need for an ongoing study of the long-term evolution of our adaptive immune response to this virus. Collective knowledge about the molecular composition of human serological IgG memory to SARS-CoV-2 is limited. Our research uses single-cell sequencing and plasma IgG proteomics to better understand the evolving plasma antibody response to infection, vaccination, and breakthrough infection.
In volunteers with a primary infection prior to vaccination, we can identify the serological recall of somatically mutated, pre-existing IgG antibodies targeting the S2 domain of the SARS-CoV-2 spike that cross-react with conserved epitopes expressed by endemic β-coronaviruses, indicating the existence of serological immune imprinting by prior infections. In contrast, in volunteers who received a full vaccine regimen and then had a breakthrough infection, the serological recall is markedly different—as shall be discussed. Collectively, these data reveal that the molecular nature of serological IgG recall appears to depend on the sequence and mode of exposure to SARS-CoV-2 spike antigen.
Supported by NIH NCI COVID-19 SeroNet grant U54-CA260543 (R.S.B.)
Activation of the aryl hydrocarbon receptor positively regulates gut migration markers on mouse B cells
Authors: Ortiz Linda F , Costa Alex B , Dekrey Gregory K 
Published: January 2023

Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that links diet and environmental factors to intestinal immune function. Activation of the AhR has been shown to enhance migration to the gut by some murine CD4+ T cells with upregulated expression of CCR9. In B cells, AhR activation has been shown to suppress B cell activation and class switch recombination (CSR), but an impact on B cell migration has not been explored. Because AhR activation can enhance fecal over serum IgA levels in mice, we hypothesized that AhR activation increases B cell migration to the gut. To test this hypothesis, we examined the expression of α4β7 and CCR9 on mouse CD19+ spleen cells in vitro. Cells were activated under conditions to stimulate CSR to IgA (poly-IgD-Dextran + LPS + TGF-β), cultured with AhR ligands for 96 hours, and analyzed by flow cytometry. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (50 nM) did not change α4β7 surface expression (mean fluorescence intensity, MFI), but the MFI for CCR9 was significantly increased by 96.7% (P &lt; 0.05) when compared to CH-223191 exposure (AhR antagonist, 100 μM). Similarly, when comparing exposure to TCDD versus CH-223191, TCDD exposure increased the percentage of α4β7+ and CCR9+ cells by 3.8% and 23.3%, respectively (P &lt; 0.05). These results suggest that enhanced migration of B cells to the gut may be positively regulated by AhR activation.
Supported by University of Northern Colorado
Defective Humoral Immunity Disrupts Bile Acid Homeostasis which Promotes Inflammatory Disease of the Small Bowel
Authors: Kubinak Jason L , Mohammed Ahmed Dawood , Mohammed Zahraa , Roland Mary , Chatzistamou Ioulia , Jolly Amy , Schoettmer Lillian , Arroyo Mireya , Kakar Khadija , Tian Yuan , Patterson Andrew , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
Mucosal antibodies maintain gut homeostasis by promoting spatial segregation between host tissues and luminal microbes. Whether and how mucosal antibody responses influence gut health through modulation of microbiota composition is unclear. Here, we use a CD19−/− mouse model of antibody-deficiency to demonstrate that a relationship exists between dysbiosis, defects in bile acid homeostasis, and gluten-sensitive enteropathy of the small intestine. The gluten-sensitive small intestine enteropathy that develops in CD19−/− mice is associated with alterations to luminal bile acid composition in the SI, marked by significant reductions in the abundance of conjugated bile acids. Manipulation of bile acid availability, adoptive transfer of functional B cells, and ablation of bacterial bile salt hydrolase activity all influence the severity of small intestine enteropathy in CD19−/− mice. Collectively, results from our experiments support a model whereby mucosal humoral immune responses limit inflammatory disease of the small bowel by regulating bacterial BA metabolism.
J.L.K. was supported by a NIAID K22 Award (AI123481), a Jeffrey Modell Network Specific Diseases Research Award, a University of South Carolina ASPIRE-I Award, a pilot project award through the University of South Carolina Center for Alternative Medicine COBRE program (P20GM103641; awarded to Drs. Mitzi and Prakash Nagarkatti), an R21 (AI142409), and 1R01AI155887.
The miseducation of T cells in autoimmunity
Authors: Kouame Elaine , Brigleb Pamela , Sangani Kishan , Dermody Terence S , Jabri Bana 
Published: January 2023

Abstract
Celiac disease (CeD) is an immune-mediated enteropathy characterized by an inflammatory T-helper type 1 (Th1) immune response against dietary gluten. Although 40% of individuals in the U.S. have the genetic factors required for the development of CeD, less than 1% will be diagnosed with CeD. This suggests that additional environmental factors are necessary for the development of CeD. Our previous work demonstrates that viral infections can disrupt tolerance to oral antigens, leading to immune activation as seen in CeD. However, the mechanisms by which viral infections trigger inflammatory responses to dietary antigen remains unknown. Here we show that upon infection with reovirus, a subset of migratory dendritic cells, cDC1, sense and uptake virally infected and necroptotic intestinal epithelial cells and secrete type I interferon (IFN), resulting in a dietary antigen specific Th1 immune response. Our results identify a novel mechanism by which certain viruses can trigger inflammatory immune responses to dietary antigen. We also demonstrate that only a subset of enteric viruses can disrupt homeostatic response to dietary antigens. Only those that both induce type I IFN, and cause necroptosis will result in such pathology. This data identifies specific viral targets for clinical intervention via vaccine that could potentially reduce the incidence of CeD and other dietary-triggered immune enteropathies. More generally, knowledge from our work enhance our understanding of how viral-host interactions drive autoimmune disorders at the mucosal interface.
Supported by grant from NIH (RO1 5R01DK098435-06)
Sensing and alarm function of vaccine-elicited SIV-gag specific CD8 TRM in the reproductive mucosa of rhesus macaques
Authors: Joag Vineet , Quarnstrom Clare , Soerens Andrew , Stolley James Michael , Schenkel Jason M , Fraser Kathryn , Vezys Vaiva , Skinner Pamela J , Hunter Eric , Bimber Benjamin , Amara Rama Rao , Masopust David 
Published: January 2023

Abstract
TRM constitute a recently identified lymphocyte lineage that occupies non-lymphoid tissues (NLT) without recirculating. Experiments in mice demonstrated that TRM reactivation triggers antiviral responses in neighboring cells by promoting local stimulation of innate and adaptive immune cells, and by recruiting immune effectors. Collectively this is referred to as ‘sensing and alarm’ function. We wished to broadly identify TRM functions in non-human primates (NHP). Here we applied a prime-boost vaccine modality in rhesus macaques to generate abundant SIVgag-specific CD8 TRM in the female reproductive tract (FRT) and 14 other NLT. To assess sensing and alarm function, macaques were challenged intravaginally with CM9 peptide from the SIV gag protein and necropsied 24 or 48 hours later. CD8 TRM reactivation increased expression of CD69 and granzyme B in SIV-gag specific CD8 T cells throughout the FRT at 24h, in situ proliferation (Ki67 expression) by 48h, and rapid antiviral and IFN response gene expression in essentially all hematopoietic and non-hematopoietic cells by 24h. Upregulation of effector genes in CD8 T cells, CD4 T cells, NK cells, and ILCs peaked at 24h and persisted at 48h. Mucosal CD4 T cells expressed various HIV restriction factors, and had reduced expression of the HIV-coreceptor CCR5. Increased numbers of vaginal T and B cells coincided with increased expression of chemokines and VCAM-1 on endothelial and stromal cells and a concomitant reduction in circulating T cells, B cells and SIV-env-specific B cells. These data demonstrate that vaccine-elicited CD8 TRM rapidly trigger local activation and the recruitment of innate, cellular, and humoral immune responses to the site of antigen exposure.
Epithelial MHC class II directs microbiota-specific intestinal immune homeostasis
Authors: Eshleman Emily M , Shao Tzu-Yu , Woo Vivienne , Rice Taylor , Whitt Jordan , Engleman Laura , Way Sing Sing , Alenghat Theresa 
Published: January 2023

Abstract
The intestinal microbiota is essential for instructing the host immune system, however, dysregulated immune responses to resident commensal microbes can promote pathologic inflammation. Despite this relationship, the mechanisms regulating tissue-intrinsic, microbiota-specific T cell responses remain poorly understood. Here, we find that non-hematopoietic intestinal epithelial cells (IECs) represent the dominant cells expressing major histocompatibility complex (MHC) II at the host-microbiota interface. Interestingly, epithelial MHCII and commensal-specific CD4+ T cells were simultaneously induced by post-natal microbiota colonization, prompting the hypothesis that epithelial MHCII regulates intestinal microbiota-specific CD4+ T cells. While classical MHCII-expressing antigen presenting cells promote antigen-specific T cell expansion, loss of IEC-intrinsic MHCII surprisingly resulted in elevated commensal-specific CD4+ T cells in the intestine. Further, epithelial MHCII actively limited accumulation of microbial-antigen specific CD4+ T cells in adult mice. Expansion of commensal-specific Th17 cells was restricted by epithelial MHCII, and remarkably mice lacking epithelial MHCII were highly susceptible to microbiota-triggered intestinal inflammation. Collectively, these data suggest that altered epithelial MHCII-T cell regulation in the intestine may impair tolerance to resident microbes and predispose to chronic inflammation. Future investigation into the relationship between the microbiota, IECs, and local immune cells could aid in the development of novel therapeutics to prevent or limit inflammatory conditions.
This research is supported by the National Institutes of Health (DK114123, DK116868 and F32AI147591 to E.M.E.), Kenneth Rainin Foundation, and Burroughs Wellcome Fund. This project is supported in part by PHS grant P30 DK078392.
Microfluidic gut-on chip system for reproducing the microbiome-immune cells interaction in Threespine Stickleback
Authors: Nouri Abdelmounaim , Rodgers Maria L , Bolnick Daniel L , Carrier Rebecca , Milligan-Myhre Kathryn , Scarpino Samuel , Steinel Natalie C 
Published: January 2023

Abstract
The development of in vitro models that mimic the immunological, mechanical, and structural properties of the gut, as well as its crucial microbial symbionts, facilitate the real-time assessment of host-microbiome interactions. Here, we describe our development of a threespine stickleback fish “gut-on-chip” biomimetic microdevice which will co-culture complex microbial communities with mucus-secreting intestinal epithelia and leukocytes. This chip was fabricated using soft lithography with liquid PDMS and consists of a middle channel coated with extracellular matrix (ECM) compounds separating two microfluidic side channels. After temperature cure, PDMS is bound on a glass slide by plasma activation, forming a closed microenvironment where cells can be grown. We have successfully isolated and independently cultured stickleback intestinal epithelial cells and leukocytes and evaluated their tolerance to various components of ECM. Our results show that fibrinogen is more suitable for culturing intestinal leukocytes compared to collagen-1 or gelatin. Leukocyte viability is more sustainable after stimulation with LPS-B5 compared to unstimulated. Unlike immune cells, stickleback epithelial cells do not survive on fibrinogen and show better viability on the collagen-1 coated medium. This study establishes the unique culture conditions necessary for teleost microfluidic gut-on-a-chip and will advance our understanding of the host-microbiome interactions in this non-model system.
Supported by Gordon and Betty More Foundation, SASI Symbiosis Model Systems #9323
Nanoparticle based depletion of Myeloid-derived Suppressor cells in Tuberculosis
Authors: Dkhar Hedwin Kitdorlang , Vantucci Casey , Enriquez Ana Beatriz , Ibegbu Chris , Vyas Shivani , Woods Nicole Alexis , Kgoadi Khanyisile , Goh Shu Ling , Roy Krishnendu , Rengarajan Jyothi 
Published: January 2023

Abstract
The bacterial pathogen Mycobacterium tuberculosis (Mtb) successfully evades host innate immune responses to cause tuberculosis (TB) disease. Recent studies showed that myeloid-derived suppressor cells (MDSCs) are recruited to the lung after Mtb infection and harbor Mtb. While MDSC-mediated negative regulation of tumor micro-environments in cancer has been extensively studied, in-depth analyses of the phenotype, functions and transcriptional signatures of MDSCs in TB are lacking. In this study we sought to characterize MDSCs in the lungs of Mtb-infected mice and develop tools for depleting MDSCs as a strategy for host-directed therapy. We determined MDSCs in the aerosol mouse model of TB and in human blood using flow cytometry. MDSCs are recruited into the lung as early as 2 weeks post-infection and expresses immunomodulatory mediators associated with immune suppression such as iNOS, IDO and arginase. We recently reported the development of novel synthetic nanoparticle antibodies (SNAbs) that specifically target and deplete MDSCs via antibody-like mechanisms. We used SNAbs to deplete Mtb-induced MDSCs in vitro and in human PBMCs ex vivo. Interestingly, we found that SNAbs efficiently depleted MDSCs in both models. To test the efficacy of SNAb-mediated depletion of MDSCs in mouse lungs in vivo, we first used a murine lung cancer model and found that intra-tracheal delivery of SNAbs successfully depleted MDSCs in vivo. Ongoing studies include evaluating the ability of SNAbs to deplete lung MDSCs following Mtb infection of mice and to assess the impact on lung T cell functions, pathology and Mtb burden. These studies will establish a platform to investigate MDSCs as a target for host-directed therapies that improve TB treatment efficacy.
Supported by grant from NIH (1R01AI155023-01A1)
PD-1 and ICOS co-expression identifies tumor-reactive CD4 Th cells in human solid tumors
Authors: Duhen Thomas , Duhen Rebekka , Fesneau Olivier , Samson Kimberly , Frye Alexandra , Beymer Michael , Rajamanickam Venkatesh , Tran Eric , Bernard Brady , Weinberg Andrew D 
Published: January 2023

Abstract
CD4 T helper (Th) cells play a key role in orchestrating immune responses, but the identity of the CD4 Th cells involved in the immune response against cancer remains to be defined. We analyzed the immune cell infiltrates of head and neck squamous cell carcinoma and microsatellite stable colorectal cancers and identified a subset of CD4 Th cells distinct from FOXP3+ regulatory T cells that co-express PD-1 and ICOS. This cell population, which was present in the tumor but absent in the periphery, features of chronic stimulation and displays characteristics of tissue-resident memory T cells. PD-1+ICOS+ tumor-infiltrating (TIL) CD4 Th cells are located primarily in the tumor stroma in proximity to MHC class II+ cells and are proliferating, suggesting local antigen recognition. The T-cell receptor repertoire of the PD-1+ICOS+ CD4 Th TIL is oligoclonal, with T-cell clones expanded in the tumor, but present at low frequencies in the periphery. Finally, these PD-1+ICOS+ CD4 Th TIL were shown to recognize both tumor-associated antigens and tumor-specific neoantigens, which were distinct from the epitopes recognized by the CD8 T cells from the same patients. Our findings provide an approach for isolating tumor-reactive CD4 Th TIL directly ex vivo and imply that harnessing the cooperation between CD4 and CD8 T cells might lead to more efficient tumor recognition and control in cancer patients.
Supported by the Providence Portland Medical Foundation and the Developmental Research Program for Head and Neck Cancer.
Third generation CAR T cells form polyfunctional long-lived memory and protect from solid-tumor relapse in an immunocompetent murine model
Authors: Reed Steven James , Dunga Meenakshi , Maylor-Hagen Heather , Kalia Vandana , Sarkar Surojit 
Published: January 2023

Abstract
Effector CAR T cell persistence and transition to memory have been widely associated with long-term protection from hematological tumor relapse. In the context of solid tumors, anti-tumor T cell exhaustion in the tumor microenvironment (TME) leads to T cell dysfunction and impaired memory formation. However, in solid tumor models a vast number of infused CAR T cells traffic to lymphoid organs (such as spleen and nondraining lymph nodes), which are bereft of CAR-antigen. The fate of these CAR T cells which have undergone ex vivo activation, viral transduction, and expansion regimens prior to transfer back into patients remains unclear. Using a third generation CAR targeting human(h)CD19t, and syngeneic murine tumor lines expressing hCD19t tumor-associated antigen, we show that CAR T cells residing in antigen-free sites of tumor-bearing immunocompetent mice transition to fully functional memory cells. Using viral infection-induced memory T cells as a benchmark, memory CAR T cells displayed hallmark memory characteristics including homeostatic proliferation, rapid polyfunctional cytokine production upon restimulation, and secondary expansion in response to cognate antigenic stimulation. Finally, memory CAR T cells in naive mice, or in mice with primary tumor remission, were protected against lethal rechallenge with heterologous hCD19t-expressing tumors. Results from this study are among the first to directly compare canonical virus-induced memory T cells with memory CAR T cells, and provide valuable insight into the characteristics and function of memory CAR T cells in an immunocompetent model for solid tumors.
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number F32CA265056, and the Pediatric Cancer Research Foundation
CAR T cells targeting Olfactory Receptor OR2H1 are an effective immunotherapeutic option in human epithelial tumors
Authors: Biswas Subir , Martin Alexandra , Galindo Carmen Maria Anadon , Mine Jessica , Payne Kyle K , Mandal Gunjan , Chaurio Ricardo , Powers John J , Sprenger Kimberly , Rigolizzo Kristen E , Innamarato Patrick , Harro Carly , Mehta Sumit , Perez Bradford A , Wenham Robert M , Conejo-Garcia Jose R 
Published: January 2023

Abstract
Chimeric antigen receptor (CAR) T cells have been successful for hematological malignancies, but so far showed limited efficiency against solid tumors. Olfactory receptors are expressed in a variety of epithelial cancers, with a limited expression in healthy tissues. We quantified olfactory receptor OR2H1 expression in ovarian cancer, non-small cell lung cancer (NSCLC), breast cancer, and many normal tissues, and we found OR2H1 is expressed in multiple solid epithelial tumors but limited to testis among healthy human tissues. CAR T cells targeting OR2H1-extracellular domain were generated, and OR2H1-specific cytotoxic killing was confirmed, both in vitro and in vivo. Correspondingly, OR2H1-CAR T cells mediate significant therapeutic effects against OR2H1+ NSCLC and high-grade serous ovarian cancer. Interestingly, OR2H1 ablation significantly delays malignant progression of at least NSCLC, but OR2H1 expression is found to be essential for the cytotoxic effects of the OR2H1-CAR T cells. In summary, T cells directed against OR2H1-expressing tumor cells could be a potential therapeutic approach in future for treating OR2H1-expressing cancers.
Supported by CA076292, R01CA157664, R01CA124515, R01CA178687, R01CA211913, U01CA232758
Inhibition of TKI-activated MIF/CXCR2 Pathway as a Novel Therapeutic Strategy in Acute Myeloid Leukemia
Authors: Hino Christopher S , Tadros Verena , Hiramoto Benjamin , Leep Benjamin , Kim Do Hyun , Reeves Mark E , Baylink David , Cao Huynh , Xu Yi 
Published: January 2023

Abstract
Despite significant advancements in our understanding of acute myeloid leukemia (AML), relapsed and refractory disease remains a major cause of treatment failure. Approximately 50% of patients with AML will develop relapsed disease following induction chemotherapy, which results in a dismal 5-year overall survival rate of 29%. The development of FMS-like tyrosine kinase 3 (FLT3) inhibitors have led to improved outcomes among patients with FLT3-mutated AML. However many patients eventually relapse and succumb to chemo-resistant disease, highlighting the need to characterize the molecular pathways which confer early TKI resistance. To explore the possible mechanisms responsible for the survival and proliferation of tyrosine kinase inhibitor (TKI) resistant blasts, we compared in vitro and ex vivo cytokine expression of gilteritinib (GILT)-treated and untreated blasts. Here we report that the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) is significantly expressed by GILT-treated blasts when compared to untreated controls. We further demonstrate that MIF expression promotes blast proliferation through the upregulation of its receptor CXCR2. Most remarkably we found that combination of CXCR2-inhibitor plus GILT works synergistically to reduce the percentage of viable blasts. Together these findings support that targeting the TKI-activated MIF/CXCR pathway could be a novel therapeutic strategy for both newly diagnosed and relapsed/refractory AML.
This study is supported by Loma Linda University GRASP and Loma Linda University Research Innovation Grant