bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel proviral function for IL-17 during gammaherpesvirus infection
Authors: Jondle Christopher Ned , Johnson Kaitlin E , Aurubin Carlie A , Xin Gang , Cui Weiguo , Huppler Anna , Tarakanova Vera L 
Published: January 2023

Abstract
Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection and are associated with B cell lymphomas. These viruses infect naïve B cells and induce a polyclonal germinal center (GC) response to establish long-term infection in memory B cells. We showed that Interferon Regulatory Factor 1 (IRF-1), an antiviral and tumor suppressor transcription factor, selectively restricts the GC reaction driven by murine gammaherpesvirus 68 (MHV68). Further, latent MHV68 infection was poorly controlled in IRF-1−/− mice, including in the peritoneal cavity where the latency is not regulated by the GC response. In our search for the mechanism underlying the observed phenotypes, we have unexpectedly found a significant increase in Th17 cells in MHV68 infected IRF-1−/− mice. Herpesvirus saimiri (HVS), a related simian gammaherpesvirus, encodes a viral IL-17, posing an intriguing possibility that IL-17 is proviral. MHV68 does not encode an IL-17 homologue, suggesting that MHV68 may rely on a host derived IL-17. Intriguingly, latent MHV68 infection was significantly attenuated in IL-17RA−/− mice establishing, for the first time, a proviral role of host IL-17 signaling during gammaherpesvirus infection. Further, there was a significant decrease in the GC B cell response in IL-17RA−/− mice following MHV68, but not LCMV infection, indicating that IL-17 signaling is selectively required to support the GC response during gammaherpesvirus infection. Altogether, our study establishes IRF-1 as a suppressor of Th17 differentiation and reveals a novel proviral role of IL-17 during gammaherpesvirus infection.
The innate signaling adaptor MAVS regulates the quality of the antibody response to West Nile Virus
Authors: Schenten Dominik , O’Ketch Marvin , Larson Cameron , Hall Brenna 
Published: January 2023

Abstract
A key difference that distinguishes viral infections from protein immunizations is the recognition of viral nucleic acids by cytosolic pattern recognition receptors (PRRs) during the course of infections. Cytosolic PRRs play a crucial role in the control of innate immunity to many viral infections. In contrast to transmembrane PRRs such as Toll-like receptors, however, the functions of cytosolic PRRs in the regulation of protective adaptive immunity have remained poorly understood. Rig-I-like Receptors (RLRs) are a family of PRRs that recognize microbial RNA in the cytosol and induce cytokine and interferon responses via the essential signaling adaptor MAVS. Infection of MAVS-deficient mice with West Nile Virus (WNV) results in a defective adaptive immune response. While this finding suggests a role for RLRs in the regulation of adaptive immunity to WNV, it is difficult to interpret due to the high WNV viremia and associated antigen loads in the absence of a MAVS-dependent innate immune response. In order to overcome these limitations, we have infected MAVS-deficient mice with a single-round-of-infection mutant of WNV. MAVS-deficient mice failed to produce an effective neutralizing antibody response to WNV despite normal titers of antibodies targeting the neutralizing lateral ridge epitope in the DIII domain of WNV-E protein. Instead, the antibodies of MAVS-deficient mice bound the neutralizing epitope with lower affinity. Our findings suggest that RLR-dependent signals are important for the quality of the humoral immune response to WNV.
Diets rich in omega-3s decrease CD8 T cell 2-dimensional affinity and short lived effector cell development and function during viral infection
Authors: Kolawole Elizabeth Motunrayo , Evavold Brian D 
Published: January 2023

Abstract
Omega-3 polyunsaturated fatty acids (n-3 PUFAs), which are key components of fish oil, are increasingly consumed for their health benefits and have been shown to dramatically influence chronic disease. Although omega-3s can lead to the production of less inflammatory metabolites, we focused on the direct effects of a high omega-3 diet on T cell activation during viral infection. Specifically, we analyzed T cell recognition of antigen and the resulting functional responses during lymphocytic choriomeningitis (LCMV) infection. The omega-3 based diet manipulated structural lipid content in plasma membranes leading to reduced T cell frequency and changes in the prevalence of immunodominant epitopes. We further found that a high omega-3 diet decreased 2D affinity and number of tetramer positive polyclonal as well as CD8 T cell receptor transgenic cells at peak anti-viral immunity. In addition to affinity, the bond lifetime of antigen recognition was also decreased. This resulted in decreased numbers of SLEC and effector cytokines without impeding viral clearance. Our work indicate that a major effect of dietary omega-3 fatty acids on T cells is the modification of the cell membrane to dampen the initial recognition of antigen leading to decreased but effective immunity.
Patients with Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have a Unique Phenotype, With Increased Activation of the PI3K/Akt/mTOR and STAT1 Pathways and Immature NK Cells
Authors: Dowdell K C , Howe Matthew , Kuehn Hyesun , Hart Geoffrey T , Hsu Amy , Su Hua , Niemela Julie , Uzel Gulbu , Shereck Evan , Schulz Laura , Feldman Tatyana , Stoddard Jennifer , Rosenzweig Sergio , Long Eric O , Dropulic Lesia , Cohen Jeffrey 
Published: January 2023

Abstract
Epstein-Barr virus (EBV) infection is usually asymptomatic and latency occurs in B cells. We studied three patients with NK cell chronic active EBV (CAEBV) disease and EBV hepatitis. All patients had an increased number of NK cells, and high levels of EBV in the blood, with EBV predominantly in NK cells; two patients who were tested had an NK cell receptor repertoire consistent with immature cells. All three patients had increased phosphorylation of Akt and ribosomal protein S6 in NK cells and a marked increase in STAT1; two of the patients had increased phosphorylation of STAT1 in their T cells, NK cells, and monocytes. Treatment of one of these patients with sirolimus, an mTOR inhibitor, reduced phosphorylation of S6 in the patient’s T and B cells, but not in her NK cells and did not reduce the level of NK cells or EBV DNA in the peripheral blood. The increased STAT1 activity observed in two of the patients was reduced to normal when the cells were treated with JAK inhibitors in vitro. Unlike other patients with STAT1 gain-of-function (GOF) mutations, no mutations were identified in STAT1 or STAT1 regulatory proteins. Patients with T or B cell CAEBV also had increased phosphorylation of Akt and S6, but not STAT1. In summary, the increase in Akt and S6 phosphorylation, and the increase in STAT1 protein, as well as immature NK cells in our NK cell patients describe a novel phenotype in NK cell CAEBV disease.
Accumulation of CXCR5+ NK cells during chronic SHIV infection is associated with enhanced viral control
Authors: Velu Vijayakumar , Rahman Sheikh abdul , Billingsley James M , Ibegbu Chris C , Shiferaw Ayalnesh , Villinger Francois J , Bosinger Steve , Johnson Paul , Amara Rama Rao , Velu Vijayakumar 
Published: January 2023

Abstract
Natural Killer (NK) cells play an essential role in antiviral immunity, however knowledge pertaining to their function in lymphoid organs during chronic HIV infection is not clearly elucidated. Lymph node (LN) follicles constitute major reservoir sites for HIV persistence. Cure strategies could benefit from the LN CXCR5+ NK cells able to access/eliminate viral reservoirs. Here we studied the phenotype, distribution and function of CXCR5+ NK cells in the LN of SHIV naive and chronic SHIV-infected (&gt;14 weeks PI) rhesus macaques (RM) and its association with plasma viral RNA levels. We found that prior to infection, a significant proportion of NK cells (~15%) expressed CXCR5. Following infection, the frequency of CXCR5+ NK cells was significantly higher in chronic SHIV-infected RM. Phenotypically CXCR5+ NK cells express higher levels of CD32a and CD16 compared to CXCR5− cells, which might be important for ADCC function. RNA expression profiling of sorted CXCR5+ and CXCR5− NK cells from LNs of chronic SHIV-infected RM revealed that CXCR5+ cells are activated and express increased levels of cytolytic markers (perforin, granzyme-B, granulysin and CD107a), suggesting that these cells have a higher capacity to kill. Gene set enrichment analysis showed elevated expression in CXCR5+ cells of transcripts associated with cell activation, TNF-alpha, Interferon signaling and apoptosis. Importantly, the higher frequency of CXCR5+ NK cells was associated with lower SHIV plasma viral RNA levels and lower germinal center Tfh cells. Thus these data suggest that CXCR5+ NK cells could play an important role in controlling chronic SHIV infection. HIV cure strategies should focus on inducing CXCR5+ NK cells that may contribute to sustained viral remission.
Identification of dendritic cell precursors in the culture of bone marrow with hematopoietic cytokines
Authors: In Hyunju , Na Hye Young , Ryu Seul Hye , Sohn Moah , Choi Wanho , Shin Hyun Soo , Park Ji Soo , Park Sejung , Park Chae Gyu 
Published: January 2023

Abstract
Dendritic cells (DCs) play crucial parts in a variety of immune responses by capturing and presenting antigens to naïve T cells and by producing the subsequent T-cell activation or tolerance. In vitro culture systems of DCs have been widely used. The culture of bone marrow (BM) in the presence of a hematopoietic cytokine, Fms-like tyrosine kinase 3 ligand (FLT3L), produces plasmacytoid DCs (pDCs) and classical DCs (cDCs), whereas the culture of BM with granulocyte-macrophage colony-stimulating factor (GM-CSF) generates DCs and macrophages considered to possess inflammatory phenotypes. In the present study, we examined the culture of BM with both cytokines, i.e., FLT3L and GM-CSF in combination and identified 4 different subsets in CD11c⁺ MHCII+ cells. Meanwhile, in the culture of BM with FLT3L, we discovered a novel population of CD11c⁺ MHCIIhi cells that possess a limited capacity of antigen-presenting activity, suggesting precursors for DCs. This novel population of DC precursors from the BM culture with FLT3L was isolated and evaluated for their potential to differentiate to DCs in the BM culture containing both FLT3L and GM-CSF. Consequently, we demonstrated that the presence of a novel population of DC precursors in the in vitro culture system of DCs.
Activation of Dendritic Cells Alters the Mechanism of MHC Class II Antigen Presentation to CD4 T Cells
Authors: Roche Paul A , Ishido Satoshi , Eisenlohr Laurence C , Cho Kyung-Jin 
Published: January 2023

Abstract
Both immature and mature DCs can process and present foreign antigens to CD4 T cells, however the mechanism by which MHC-II in mature DCs acquires antigenic peptides remains unknown. To address this we have studied antigen processing and presentation of two distinct CD4 T cells epitopes of the influenza virus haemagglutinin coat protein by both immature and mature DCs. We find that immature DCs almost exclusively use newly-synthesized MHC-II targeted to DM+ late endosomes for presentation to influenza virus-specific CD4 T cells. By contrast, mature DCs exclusively use recycling MHC-II that traffics to both early and late endosomes for antigenic peptide binding. Knock-down of the small GTPase Rab11a partially inhibits recycling of MHC-II in mature DCs and inhibits presentation of an influenza virus hemagglutinin CD4 T cell epitope generated in early endosomes. By contrast, knock-down of Rab11a does not affect presentation of an influenza virus hemagglutinin CD4 T cell epitope that is DM-dependent and is generated in late endosomes in both immature and mature DCs. These studies highlight a “division of labor” in MHC-II peptide binding in which immature DCs preferentially present antigens acquired in Rab11a− DM+ late endosomes whereas mature DCs use recycling MHC-II to present antigenic peptides acquired in both Rab11a+ early endosomes and Rab11a− endosomes for CD4 T cell activation.
Activation of virtual memory CD8+ T cells specific for self antigens requires antigen presentation by CD11c+ cells
Authors: Gillig Marc A , Karandikar Sukrut H , Srivastava Pramod K 
Published: January 2023

Abstract
Even in experimentally naïve mice, a significant fraction of CD8+ T cells express CD44, a marker associated with previous exposure to cognate antigen. Many of these cells express additional hallmarks of the memory phenotype, leading to questions about their specificity, development, and functional relevance. It has been suggested that lymphopenic conditions experienced by early T cells in prenatal/neonatal mice can give rise to these unexpected “virtual” memory T cells. However, their antigen specificity remains largely unknown. Here, we report several peptide sequences derived from self antigens, which are capable of eliciting robust interferon gamma (IFNγ) secretion in CD8+ T cells isolated from naïve mice. Only CD44+ (memory phenotype), and not CD44− (naïve phenotype) T cells show this unexpected self-reactivity, and the antigens are cross presented by professional antigen-presenting cells (pAPCs) but are not presented to T cells by non-pAPCs expressing these antigens. Interestingly, antigen donor cells pretreated with IFNγ also failed to stimulate these T cells. The implications of having such self-reactive memory-phenotype T cells in circulation remain unclear, although their role in autoimmunity and self-tolerance can be imagined. There is also the possibility that such responses are a manifestation of immunological nihilism.
TGF-β downregulates MHC I surface expression through a Smad3-dependent mechanism
Authors: Berglund Alix K , Long Julie M , Schnabel Lauren V 
Published: January 2023

Abstract
Major histocompatibility complex (MHC) expression is tightly regulated in nucleated cells to prevent unnecessary and damaging immune responses. Transforming growth factor-β (TGF-β) has previously been shown to downregulate MHC I surface expression, although this mechanism is unknown. We hypothesized that TGF-β downregulates MHC I gene expression thereby inhibiting MHC I surface expression. TGF-β1, TGF-β2, and TGF-β3 were all similarly effective at downregulating constitutive MHC I expression. Inhibition of TGF-βRII (ALK5) or Smad3 prevented downregulation of MHC I surface expression by TGF-β indicating this mechanism is through canonical TGF-β signaling. RNA-sequencing revealed that TGF-β significantly downregulated gene expression of accessory proteins necessary for stable MHC I protein expression including β2-microglobulin (B2M). qPCR confirmed that B2M expression was significantly lower in TGF-β-treated MSCs compared to untreated, while MHC I gene expression was not significantly different. However, downregulation of B2M gene expression did not occur until at least 24 hours after TGF-β treatment suggesting an intermediate step may be involved between Smad3 activation and downregulation of B2M. These results support that TGF-β regulates MHC I surface expression by downregulating gene expression of proteins associated with antigen processing and presentation through a Smad3-dependent pathway. Further investigation is needed to analyze which antigen processing and presentation genes regulated by TGF-β are the limiting factor for MHC I surface expression and how Smad3 influences expression of these genes.
Liposomes represent a perfect tool to enhance the cross-presentation effectivity of viral HIV-1 p24 protein fused with heat shock protein 70
Authors: Zachova Katerina , masek Josef , Bartheldyova Eliska , Krupka Michal , Kulich Pavel , Turanek Jaroslav , Raska Milan 
Published: January 2023

Abstract
Current approaches focusing on anti-viral and anti-tumor vaccines developement tend to induce strong CD4 T cell response leading in antibodies production and simultaneously, efficient CD8 T cell activation responsible for cytotoxic elimination of infected cells. The p24 protein from HIV-1 virus is a relatively conserved but poorly immunogenic protein. Its fusion with host heat shock protein 70 (hsp70) enhanced the immune response to p24 including cross-presentation on MHC I molecules, despite the recognition by antigen presenting cells as an exogenous antigen. Cross-presentation efficacy and immune response was supported by binding this construct to liposomes containing aminooxy lipids allowing further modification by click chemistry. Hsp70-p24 was bound to liposome surface and used in cDC1 cell line (DCs from murine spleen) and mice vaccination model. Activation markers, MHCI expression, apoptosis assay and proliferation efficacy was analyzed. Expression of DC cell-surface activation markers CD40, CD86 and also MHC I was increased in hsp70-p24 pulsed cells as much as LPS, but when antigens coupled to liposome expression was significantly higher. None of the constructs activated CD86 expression as much as the LPS. Studies on hepatocytes transfected by hsp70-p24 encoding plasmid DNA showed increased death of hepatocytes co-cultivated with splenocytes from mice vaccinated by hsp70-p24-liposome in comparison to hsp70-p24 alone. Activation markers on CD8 T cells from vaccinated mice were enhanced after co-cultivation with hsp70-p24-liposome pulsed cDC1 cells or bone marrow derived dendritic cells. All these results clearly show that coupling of antigen with liposomes leads to effective CD4 and also CD8 T cell activation.
Unusual distribution of a non-classical MHC I restricted CD8+ T population
Authors: Guan Jian , Shastri Nilabh 
Published: January 2023

Abstract
The normal peptide repertoire presented by MHC class I molecules on the cell surface is essential for immune surveillance of intracellular pathogens. The generation of this peptide repertoire is critically dependent upon the ER aminopeptidase associated with Ag processing (ERAAP). Interestingly, ERAAP-deficient cells are recognized by a unique population of cytotoxic T cells, called QFL-T cells, that are specific for the ligand presented by the non-classical MHC molecule, Qa-1b. The QFL-T cells are similar to other non-classical MHC restricted NKT or MAIT cells in their αβ TCRs, but their physiological function(s) are unknown. To identify the potential function of QFL-T cells, we assessed the expression of the Qa-1b restricted ligand as well as the distribution of QFL-T cells in various tissues. We found the ERAAP-dependent Qa-1b restricted ligand as well as the QFL-T cells were highly expressed in the intestine. Remarkably, relative to wild-type mice, the overall number and frequency of QFL-T cells among the intraepithelial lymphocytes(IELs) decreased significantly in the germ-free mice whereas the splenic QFL-T population remained unaffected. These findings suggest a role for gut-microbiota in the homing/maintenance of the QFL-T cells in the intestine.
The (tremendous) gap between predicted epitopes and those actually recognized by CD8 T cells
Authors: Kirchenbaum Greg A , Lehmann Alexander , Lehmann Paul V 
Published: January 2023

Abstract
In order to monitor CD8 cell immunity it is essential to know the peptide determinant(s) of the antigen that these T cells recognize. Relevant peptide determinants of antigens were initially identified through characterization of T cell lines or hybridomas, but more recently they are increasingly predicted based on MHC-peptide binding algorithms. Systematic, brute force testing of the actually engaged CD8 T cell repertoire ex vivo is an alternative approach, but has been challenging due to (a) the large number of candidate peptides for even simple antigens, (b) the volume of blood required for testing these peptides, and (c) the scope of effort being at the border of feasibility. To highlight the utility of ELISPOT to perform such epitope mapping, we performed a feasibility study in which PBMC from HCMV infected, HLA-A*02:01 subjects were assessed for reactivity against the 553 individual nonamer peptides that encompass the entire HCMV pp65 protein. Reactivity against a single peptide of the HCMV pp65 protein, pp65495–503, was of particular interest because numerous reports have indicated that this peptide is immunodominant in HLA-A*02:01 subjects. Strikingly, our epitope mapping showed that pp65495–503 was immunodominant in only a fraction of our HLA-A*02:01, HCMV infected test subjects. Instead, responses to pp65495–503 were either subdominant or absent in other HLA-A*02:01, HCMV infected test subjects. In the latter subjects, other peptides of pp65 elicited robust responses, providing further confirmation of HCMV status. Collectively, our findings suggest that systematic testing against all potential epitopes of the antigen of interest is both feasible and is needed for reliably monitoring of T cell immunity.
Structural Insights into the Mechanism(s) of Peptide Loading in MHC-I dependent Antigen Presentation
Authors: Jiang Jiansheng , Natarajan Kannan , Kim Ellen , Dhobi Javeed A. , Mage Michael G. , Boyd Lisa F. , Margulies David H. 
Published: January 2023

Abstract
Class I MHC molecules (MHC-I) provide crucial cell surface elements that signal health or status of cells for recognition by T cells via their T cell receptor or natural killer (NK) cells via various NK receptors. MHC-I dependent antigen presentation thus influences TCR and NK recognition in immunity to infection, in cancer, and in autoimmunity. Antigen presentation in the MHC-I-dependent pathway depends, in part, on the loading of peptides, derived from proteolysis, aberrant translation, or protein splicing onto MHC-I molecules in the endoplasmic reticulum (ER). The classical pathway of peptide loading and exchange involves components of the peptide loading complex (PLC): the transporter TAP1/2; a lectin, calreticulin; an oxidoreductase, ERp57; a chaperone, tapasin; as well as the peptide-receptive MHC-I molecule and its light chain, b2-microglobulin (b2m). To understand the mechanism of peptide loading and exchange, several laboratories have explored functional and structural aspects of MHC-I interactions with a tapasin homolog, TAP binding protein, related (TAPBPR). We previously reported the structure of a TAPBPR/MHC-I complex at 3.4 Å resolution. However, details of the direct interaction of tapasin with MHC-I are more desirable. Here we report the X-ray crystal structure of tapasin/MHC-I complexes at higher resolution. We discuss similarities and differences between the tapasin/MHC-I and TAPBPR/MHC-I interactions and their implications for MHC-I dependent T cell and NK cell recognition.