bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hilar node CD5+ B cells from tolerant mice inhibit allergic airway disease in sensitized recipients (97.14)
Authors: Schramm Craig , McNamara Jeff , Singh Anurag , Secor Jr Eric , Guernsey Linda , Thrall Roger 
Published: January 2023

Abstract
Ovalbumin (OVA)-sensitized mice develop allergic airway disease (AAD) with 7-10 days of OVA aerosol exposure but then have resolution of disease and development of local inhalational tolerance (LIT) after 6 weeks of continued aerosols. We have shown that B cells isolated from hilar lymph nodes (HLN) of mice at LIT and adoptively transferred to OVA-sensitized mice inhibit AAD in the recipient animals due to induction of CD4+Foxp3+ regulatory T cells (J Immunol 2008; 180:7318-26). The present study continued to address the phenotype of these suppressive B cells. CD19+ cells were isolated from LIT HLNs and were separated into CD5+ and CD5- populations by flow cytometry. Cells were adoptively transferred to OVA-sensitized C57BL/6 mice (6-8 in each group), which were then exposed to 1% OVA aerosols for 7 days. Mice receiving LIT HLN CD5+ B cells had significantly less airway eosinophilia (61 ± 2%; 17 ± 3 x 105 cells) than mice receiving saline (74 ± 2%; 31 ± 4 x 105 cells) or LIT HLN CD5- B cells (76 ± 3%; 30 ± 4 x 105 cells; p &lt; 0.05 for each by ANOVA). The number of airway CD4+Foxp3+ T cells was increased in animals receiving HLN CD5+ B cells (7.0 ± 0.7 x 104 cells) compared to those receiving saline (4.9 ± 0.7 x 104 cells) or HLN CD5- B cells (4.7 ± 0.7 x104 cells; p &lt; 0.05). Thus, regional CD5+ B cells in HLNs of LIT mice increased CD4+Foxp3+ expression and inhibited AAD in adoptively transferred animals.
Opioid receptors are targets for alleviation of allergen-induced diarrhea and modification of immune parameters in mice (97.3)
Authors: Duncker Swantje , Philippe David , Mercenier Annick , Nutten Sophie 
Published: January 2023

Abstract
So far, allergen avoidance is the most efficient treatment for individuals suffering from food-allergies. Since this almost always results in impairment of quality of life, new therapeutic concepts are needed. As opioid receptor (OR) expression has been demonstrated on various immune cells and as they have been shown to influence intestinal inflammation and motility, we were interested to study if OR are also involved in allergen-induced diarrhea. Ovalbumin-sensitized (OVA) Balb/c-mice were orally challenged with OVA, resulting in transient diarrhea and changes of plasma total IgE, OVA-specific IgE and mouse-mast-cell-protease-1(MMCP-1). Animals were pre-treated with kappa- or mu-OR-agonists (U50’488, DAMGO) and/or OR-antagonist and results were compared to controls. U50’488 and DAMGO significantly delayed the onset and decreased the severity of OVA-induced diarrhea. Animals receiving U50’488 showed lower total IgE and MMCP-1 concentration compared to controls, whereas DAMGO only showed a minimal influence on MMCP-1 release. The positive effect on diarrhea severity was partially reversed by pre-treatment with OR-antagonists. To our knowledge this is the first time that ORs are implicated as targets in modulation of food allergy. The changes in immune parameters with one of the OR-agonist suggest mechanisms extending beyond local intestinal motility and secretory regulation. Targeting of kappa- and/or mu-OR might prove valuable in alleviation of food allergies in the future.
Ischemia-reperfusion induces interferon-regulatory-factor-4 in renal dendritic cells which suppresses postischemic inflammation and prevents acute renal failure. (98.1)
Authors: Lech Maciej , Lassen Saraswati , Römmele Christoph , Mittruecker Hans-Willi , Mak Tak , Anders Hans-Joachim 
Published: January 2023

Abstract
Acute renal failure is still a serious medical problem that causes substantial morbidity and mortality. Ischemia-reperfusion (IR) activates TLRs causing inflammation and kidney injury. We hypothesized that certain factors suppress dendritic cell activation and thereby limit sterile renal inflammation, e.g. interferon-regulatory-factor (IRF)-4. Bi- or unilateral renal clamping was carried out for C57BL/6 (WT) and IRF4-knockout (IRF4-/-) mice. Known functions of the transcription factor IRF4 are the maturation of B cells, T cells and macrophages. Oxidative stress induced IRF4 expression in myeloid cells in-vitro as well as in the postischemic kidney. Lack of IRF4 aggravated acute renal failure after renal artery clamping together with increased intrarenal expression of TNF-α, IL-6, CXCL2, and CCL2 as well as excessive tubular necrosis and neutrophil influx. Consistent with these results we observed higher creatinine and urea levels in the serum of IRF4-/-mice after IR. This effect almost entirely depended on the role of IRF4 to suppress TNF-α release by intrarenal dendritic cells. Both clodronate depletion of these cells and TNF-α blockade with etanercept entirely abrogated the aggravation of cytokine expression and acute renal failure in Irf4-deficient mice. Thus, loss-of-function mutations in the IRF4 gene predispose to IR injury because the postischemic induction of IRF4 in resident dendritic cells suppresses them to secrete TNF-α and thereby limits immunopathology.
Docosahexaenoic acid inhibits cytokine production in dendritic cells and modulates T cell differentiation (98.6)
Authors: Kong Weimin , Yen Jui-Hung , Adhikary Sabina , Toscano Miguel , Ganea Doina 
Published: January 2023

Abstract
Protective anti-inflammatory effects of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were reported in clinical studies and animal models of colitis, sepsis, and stroke. In the present study we investigated the effects of DHA on the function of bone marrow-derived dendritic cells (DC) and CD4+ T cells. Our studies show that pretreatment with DHA prevents LPS-induced DC maturation, maintaining an immature phenotype characterized by low expression of MHCII and costimulatory molecules, and high levels of endocytosis. Exposure to DHA inhibits the production of proinflammatory cytokines and chemokines such as IL-6, TNFα, CCL-4, and IL-12p70. In addition, we report here for the first time that DHA has a similar inhibitory effect on IL-23 and IL-27, two other members of the IL-12 family. DHA exerted a similar inhibitory effect on IL-12 and IL-23 expression in vivo in LPS-inoculated mice maintained on a DHA-enriched diet. We also investigated the effects of DHA on T cells and found that DC treated with DHA (DC-DHA) have poor stimulatory capacity for T cells. T cells activated by DC-DHA also showed low levels expression of IFNα and IL-17, and high levels of Foxp3. Based on the inhibition of proinflammatory cytokine release and reduction in T cell stimulatory capacity, we conclude that DC are important targets for the anti-inflammatory activity of n-3 fatty acids.
The rheumatoid arthritis shared epitope is a potent helper T cell-polarizing ligand (98.8)
Authors: Almeida Denise , Ling Song , Pi Xujun , Hartmann-Scruggs Anne , Pumpens Paul , Holoshitz Joseph 
Published: January 2023

Abstract
Recent evidence strongly implicates IL17-producing helper T (Th17) cells in the pathogenesis of rheumatoid arthritis (RA) and other autoimmune conditions. Susceptibility to RA and disease severity have long been shown to associate with a HLA-DRB1-encoded 5 amino acid sequence motif, called the shared epitope (SE), however, the mechanistic basis of SE-RA association remains unknown. We have previously sown that the SE acts as an allele-specific ligand that triggers innate immune signaling in other cells. In order to gain better insights into the impact of the SE on immune regulation, we have studied its effect on helper T cell polarization in vitro. Here we show that when added to the CD8+ subset of dendritic cells (DCs), the SE ligand inhibits the enzymatic activity of indoleamine 2,3 dioxygenase (IDO), a key tolerogenic enzyme. When SE-activated DCs were co-cultured with naïve CD4+ T cells, they enhanced the differentiation to Th17 cells, and inhibited generation of Foxp3+ T regulatory cells (Tregs). The SE effect could be seen with peptidic SE ligands, but even more potently, when the SE was presented in its natural tri-dimensional conformation as part of HLA-DR tetrameric proteins. Our data demonstrate a previously unknown immune regulatory effect of the SE ligand that may provide important clues about its functional role in RA.
Transmembrane domain interaction regulates HLA-DO inhibition of HLA-DM (100.20)
Authors: Yoon Taejin , Macmillan Henriette , Roh Sujin , Mellins Elizabeth 
Published: January 2023

Abstract
Peptide-loading of MHC class II (e.g. HLA-DR) is regulated by the peptide exchange catalyst, HLA-DM (DM). HLA-DO (DO) inhibits DM, but the mechanism is not established. We found that a DMB point mutant with aberrant glycosylation at DMβ108 failed to co-precipitate with DR3 at pH 5, but was able to bind DO at this pH, and conversely, precipitated with DR3, but not with DO, at pH 7. Additional mutants implicated a unique region of DMβ in DO binding, distinct from but near the putative DR interface in human B cell line. However, FRET assay results with soluble recombinant proteins are inconsistent with these observations and argue that DO binds to a surface overlapping with the DR binding surface on DM. These contradictory results suggested that the transmembrane (TM) regions influence the interaction between DM and DO. We found that TM regions of DM and DO contain not only αβ dimerization motifs, but also intermolecular interaction motifs. A DM TM mutant with reduced DO interaction showed increased DM function in cells, suggesting that TM interaction between DM and DO regulates DO inhibition of DM. Taken together our results suggest DO inhibition is noncompetitive in cells and are consistent with previous evidence for a trimolecular complex (DR/DM/DO) in a B cell line.
Presentation of immunodominant epitopes from mixture of protein antigens is hierarchial (100.21)
Authors: Kim Ae , Hartman Isamu , Lanar David , Boronina Tatiana , Cole Robert , Sadegh-Nasseri Scheherazade 
Published: January 2023

Abstract
Immunodominance is defined as restricted responsiveness of T cells to a few selected epitopes from complex antigens. We have established a reductionist cell-free antigen-processing system for MHC class II that constitutes five purified components: HLA-DR1, HLA-DM, and three cathepsins. This system successfully identified the physiologically selected epitopes from two model antigens. When applied for de novo epitope identification to LSA-NRC of malaria, or HA1-H5N1 (Avian Flu), the system selected epitopes that were confirmed to be immunodominant by their capacity to activate CD4+ T cells in HLA-DR1 positive human volunteers or transgenic mice (Hartman/Kim, et al. Nat Med 16, pp1333-1340 (2010). To evaluate our system to a mixture of the above antigens, the system identified the epitopes from both antigens. We tested the immunogenicity of epitopes and the parent proteins in HLA-DR1 transgenic mice immunized with the mixture of both HA1 and LSA-NRC in a recall T cell proliferation assay. T cells responded only to the HA1 and its immunodominant epitope, while little, if any stimulation against LSA-NRC and its dominant epitope were measured. These observations did not change even when the ratio of LSA-NRC:HA1was 2:1. These findings show a hierarchy for the selection of immunodominant epitopes of different proteins during antigen processing, which can be important in design of combination vaccines.
HLA class II (HLA-DQ) protein stability profile and disease association (100.23)
Authors: Miyadera Hiroko , Tokunaga Katsushi 
Published: January 2023

Abstract
HLA (Human Leukocyte Antigen) is the most important genetic loci in relation to disease predisposition with autoimmune, infectious, and numerous other disorders, as revealed by genome wide association studies. Although allele specific antigen presentation has been believed as the major functional determinant implicated in diseases, the highly promiscuous antigen binding to disease associated and non-associated alleles in many autoimmune disorders suggest the contributions of multiple other factors in HLA-predisposition to diseases. The precise mechanisms by which particular HLA alleles exert disease condition thus remain uncovered for most of these disorders. In this study we have established a cell-based, highly quantitative assay to measure the cell surface protein expression levels of HLA class II, that might reflect their protein stability levels. The comprehensive picture on the HLA-DQ protein stability profile will be presented and discussed with regard to the allele specific polymorphisms and disease associations, as well as the haplotype evolution of HLA-DQ loci.
N-glycosylation of MHCII alters presentation of commensal carbohydrate antigens (100.24)
Authors: Ryan Sean , Cobb Brian 
Published: January 2023

Abstract
In conditions of dysregulated inflammatory responses, such as inflammatory bowel disease, recent studies have suggested that oral treatment with the capsular polysaccharide A (PSA) from the intestinal commensal Bacteroides fragilis promotes regulatory CD4 T cells and reduces disease pathology, yet the endogenous mechanisms of PSA immune activation remain unclear. Unlike traditional T cell-independent polysaccharide antigens, we have characterized a group of T cell-dependent antigens (T-glycoantigen) including PSA that are processed and presented within the MHCII pathway for CD4 T cell recognition. However, unlike prototypical peptide antigens, we have found that T-glycoantigen presentation is sensitive to the N-glycosylation state of MHCII. Furthermore, we have defined a key glycosyltransferase in antigen presenting cells that is necessary for T-glycoantigen presentation, but is dispensable for peptide antigen. We have translated this discovery into a novel mouse model to define the mechanisms behind the potential therapeutic role of PSA-specific T cell responses in health and disease. Our results provide evidence for the role of B. fragilis colonization in immune homeostasis and its potential use as a “probiotic” therapy to modulate dysregulated immune systems in inflammatory diseases. (Supported by grants OD004225 and GM082916 to BA Cobb)
Antigen presentation in the CNS during EAE (100.26)
Authors: Sosa Rebecca , Murphey Cathi , Cardona Astrid , Forsthuber Thomas 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis (EAE) shares many similarities with the acute inflammatory episodes of human Multiple Sclerosis (MS) both clinically and histopathogically and has therefore been instrumental in defining the sequence of events that occur in MS. It is well established that CD4+ T cells specific for myelin antigen (Ag) can induce EAE in susceptible animals. Dendritic cells (DCs) and microglia are both capable of priming CD4+ T cells against myelin Ag via presentation by MHC class II molecules present on their cell surface. However, it has remained unclear precisely how infiltration of inflammatory cells into the CNS during EAE relates to the kinetics of myelin antigen uptake and presentation by specific APCs. In this study we have investigated which APCs are loaded with myelin antigen in the naïve brain as well as in the immunogenic context of EAE. Our results reveal that a low percentage of microglia are already pre-loaded with myelin Ag even in naïve mice and are capable of presenting Ag immediately for T cell activation following immunization. Several days after immunization a large influx of myelin-loaded DCs appears, coinciding with the onset of clinical disease. This data suggests that low-level presentation of myelin Ag by CNS-resident microglia may play a role in the induction phase of EAE, although the mechanism by which these cells have acquired Ag remains unresolved.
Peptide-MHC stability regulates the efficiency and duration of cross-priming (100.4)
Authors: Watson Alan , Mylin Lawrence , Thompson Megan , Schell Todd 
Published: January 2023

Abstract
Mechanisms that regulate the recruitment and the accumulation of T cells can impact the magnitude of determinant-specific responses. In this study, we demonstrate that peptide-MHC stability is a regulator of CD8+ T cell cross-priming. We find that increasing the kinetic stability of pMHC for an immunorecessive determinant from SV40 large T antigen, designated site V, overcomes the immunorecessive nature of the determinant. Using an in vivo assay to measure the proportion of naïve T cells that are triggered by cross-priming, we found that enhanced immunogenicity was due to two independent mechanisms regulated by pMHC-stability. 1) Enhanced cross-priming resulted in more efficient recruitment of site V-specific T cells, and 2) extended duration of cross-priming was associated with greater accumulation of site V-specific T cells. Thus, our results suggest that pMHC-stability regulates the magnitude of the CD8+ T cell response by influencing the number of naïve T cells recruited and the extent of T cell expansion. These findings have implications for the design of multivalent CD8+ T cell vaccines targeting subdominant determinants.
Crystal structure of human CD4 complexed with MHC class II, peptide and T cell receptor (100.47)
Authors: Yin Yiyuan , Wang Xin , Mariuzza Roy 
Published: January 2023

Abstract
The recognition of agonist peptide and MHC class II by T cell receptor (TCR) triggers the activation and development of CD4+ T cells. CD4, as the co-receptor, plays an important role in T cell signaling. Wild-type CD4 contacts the non-polymorphic domains of MHC class II with remarkably low affinity. By using an affinity-matured CD4 molecule, we determined the X-ray crystal structure of the ternary complex between the four Ig-like domains of human CD4 (D1-D4) and a TCR bound to HLA-DR4 bearing an agonist peptide (pMHC). The structure precludes direct CD4-TCR contacts, but provides ample room for the placement of CD3 subunits. Importantly, the CD4-pMHC-TCR complex is incompatible with models for TCR triggering involving MHC or CD4 dimerization. On the other hand, it is compatible with a recent model for T cell activation involving TCR dimerization via the Cα domain. The structure also suggests that non-canonical TCR docking modes, such as those observed in certain autoimmune TCR-pMHC complexes, may affect the association with CD4 and thereby alter T cell triggering. Collectively, our results provide a picture of the CD4-pMHC-TCR signaling complex that will be useful for understanding the initiation events of T cell activation.
Cryptic tRNAi shapes the pMHC I repertoire (100.5)
Authors: Starck Shelley , Jiang Vivian , Pavon-Eternod Mariana , Prasad Sharanya , Pan Tao , Shastri Nilabh 
Published: January 2023

Abstract
MHC class I molecules present peptides on the cell surface for immune surveillance of viruses and cancer. Interestingly, the peptides are encoded not only in conventional AUG-initiated translational reading frames but also in non-AUG initiated cryptic reading frames. Whether the same or distinct translational machinery is used to produce cryptic peptides at non-AUG start codons, such as CUG, is not known. Here, we show that translational initiation of antigenic precursors at cryptic CUG codons is differentially regulated by ribosomal initiation complexes that contain novel initiator tRNAs. This tRNA is distinct from Met-initiator tRNA and enhances initiation at CUG start codons. Thus, a novel tRNA -based mechanism can supply peptides for presentation by MHC I.
Oxidative stress compromises endosomal antigen processing in aging APC (100.50)
Authors: Santambrogio Laura , Cannizzo E. Stefania , Clement Cristina 
Published: January 2023

Abstract
In aging, higher production and defective clearance of reactive oxygen species leads to the accumulation of oxidatively damaged biomolecules. Herein we demonstrate that splenic APC purified from old mice accumulate aggregates of oxidatively damaged proteins in endosomal compartments that are not found in young mice. MS/MS analysis determined that oxidized aggregates comprised both endogenous and exogenous proteins post-translationally modified by side chain carbonylation (mono and di-oxidation), nitrosylation and advanced glycation end products. Following in vivo immunization, aggregate accumulation interfered with efficient endosomal degradation and antigen processing due to interaction between the immunizing antigen and the misfolded carbonylated proteins. Treatment with anti-oxidants partially restored the adaptive immune response to the immunizing antigen. We propose that endosomal inefficiency, due to deposits of aggregated, misfolded and heavily oxidized proteins contributes to adaptive immunosenescence associated with aging, and that targeting drug, promoting the clearance of oxidized moieties, lead to partial reversion of this process.
IL-4- and IL-10-producing invariant NKT cells inhibit Th1 but not Th17 cells, while IFN-γ-producing invariant NKT cells minimally regulate Th1/Th17 response in experimental autoimmune encephalomyelitis (101.10)
Authors: Oh SaeJin , Chung Doo Hyun 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis (EAE) is regulated by Th1 and Th17 response. Invariant (i) NKT cells prevent EAE, depending on IL-4, IL-10, and IFN-γ. However, which cytokines produced by iNKT cells regulate Th1 and/or Th17 response in EAE remains unclear. To address this issue, B6 and Jα18-/- mice were immunized with MOG35-55 peptide. Jα18-/- mice showed higher clinical scores, IL-17 and IFN-γ transcript, and intracellular IL-17 and IFN-γ+CD4+ T cells in CNS than B6 mice, which was reduced by adoptive transfer of wild type or IFN-γ-deficient iNKT cells. Adoptive transfer of IL-4- or IL-10-deficient iNKT cells into Jα18-/- mice decreased IL-17 transcript, and intracellular IL-17+CD4+ T cells in CNS but not clinical scores, IFN-γ transcript, and intracellular IFN-γ+CD4+ T cells. Taken together, IL-4- and IL-10-producing iNKT cells inhibit Th1 but not Th17 response in CNS during EAE. Moreover, IFN-γ-producing iNKT cells minimally regulate Th1 and Th17 in EAE.
Loss of CIKS/Act1, the signaling adaptor for IL-17 family cytokines, significantly ameliorates development of fatal disease in the Fcgamma RIIB-deficient mouse model for lupus (101.18)
Authors: Pisitkun Prapaporn , Ha Hye-Lin , Claudio Estefania , Tivy Caitlyn , Wang Hongshan , Siebenlist Ulrich 
Published: January 2023

Abstract
CIKS (Act1 or TRAF3IP2) is an adaptor protein required for signaling by receptors of the IL-17 family of cytokines. CIKS has been shown to be vital for disease in autoimmune mouse models of CIA and EAE. IL-17A may promote spontaneous germinal centers formation in the lupus prone BXD2 mice. However, the significance of IL-17 cytokines in the clinical outcome of lupus disease has never been addressed. Here we show that Th17 cell numbers are increased in Fcgr2b-deficient mice and IL-17 cytokine signaling is critically involved in disease development in this lupus model. Loss of CIKS significantly reduced mortality rates in Fcgr2b-deficient mice. Unexpectedly, the reduced mortality was not correlated with lower levels of antibodies to ANA or anti-dsDNA. Nevertheless, loss of CIKS on an FcgR2b-deficient background did reduce the formation of spontaneous germinal centers, which correlated with a diminished rate of isotype switching and plasma cell differentiation; furthermore, the generation of T-cell effectors was slowed. Most importantly, loss of CIKS profoundly reduced severe glomerulonephritis and inflammatory cell infiltrations in kidneys, key events in the fatal outcome of the lupus-like disease in Fcgr2b-deficient mice. These novel findings suggest that IL-17 family cytokines signaling via CIKS play critical roles in the pathogenesis of lupus disease in Fcgr2b-deficient mice; these findings also position CIKS as a potential new target for therapeutic intervention in SLE.