bluuebunny/crossref_metadata_2025_split huggingface dataset:
The link between multiple sclerosis, T regulatory cells and Japanese rice (96.1)
Authors: Wormser Uri , Brodsky Berta , Proscura Elena , Erlanger-Rosengarten Avigail , Shapira Elena 
Published: January 2023

Abstract
The purpose of the present study was to develop a peptide for treatment of multiple sclerosis (MS). We have tested the effect of a novel antiinflammatory peptide (KGHYAERVG, termed IIIM1) on experimental autoimmune encephalitis (EAE), an animal model of MS. Our findings demonstrate significant reduction in neurological score following oral administration of IIIM1, as compared to the control groups received the vehicle (saline). Structural studies revealed that the entire peptide is required for activity. The peptide caused significant reduction in IL17, interferon gamma and IL12 production by isolated splenocytes and concomitant elevation of antiinflammatory cytokines. IIIM1 elevated T regulatory cells (Tregs, CD4+CD25+FoxP3+) in brain and spleen of EAE mice. Similar proliferative effect was observed in isolated human and mouse Tregs in vitro. Stimulation of Tregs by IIIM1 caused production of a new peptide termed RA1 present in Oryza Sativa Japonica group. This Japanese rice peptide ameliorated neurological symptoms in the EAE model. Similar beneficial effect was observed upon oral administration of an extract of Japanese rice. In conclusion, oral treatment with IIIM1 ameliorates EAE symptoms via stimulation of Tregs to proliferate and produce RA1 which reduces EAE symptoms. These findings may explain the relatively low prevalence of MS in Japan and other Japanese rice-eating populations. (This work was supported in part by The Israel Science Foundation grant 747/05).
Therapeutic effect of lithium in EAE: Effects on dendritic cells and encephalitogenic activity of T cells. (96.16)
Authors: Buel Amber , Naves Rodrigo , Mbana Tethia , Raman Chander , De Sarno Patrizia 
Published: January 2023

Abstract
We have reported that the GSK3 inhibitor, lithium, is therapeutic in acute and relapsing remitting EAE. We have now determined that lithium treatment is effective in attenuating EAE induced by Th1 encephalitogenic T-cells but not Th17 cells. These results were obtained from passive transfer experiments in which encephalitogenic Th1 or Th17 cells were transferred into lithium-treated or untreated naïve recipients. Consistent with this observation, lithium treatment was also ineffective in inhibiting EAE in IFN-γR1-/- mice. Various experiments indicated that the primary target of lithium therapy in vivo were cells of the innate immune system such as, dendritic cells (DC) rather than T-cells. Using primary dendritic cells obtained from spleens and lymph nodes or bone marrow derived DC (BMDC), we have determined that lithium does not affect LPS or CpG-induced maturation of DC. Remarkably, lithium treated DC were as or more efficient than untreated DC in their ability to process and present ovalbumin to OTII T-cells or MOG35-55 peptide to T-cells from 2D2 TCR transgenic mice. These observations raise the possibility that lithium-treatment of DC alters the chemokine and cytokine profile involved in migration and/or Th-subset specific differentiation. Overall, our findings that pharmacological inhibition of GSK3 is effective in Th1 EAE but not Th17 EAE has crucial implications for identifying and treating MS patients.
Deletion of C-reactive protein exacerbates collagen-induced arthritis: A role for CRP in immune tolerance? (96.23)
Authors: Jones Nicholas , Landis Dawn , McCrory Mark , Szalai Alexander 
Published: January 2023

Abstract
Heightened C-reactive protein (CRP) blood level associates with inflammation and tissue damage in rheumatoid arthritis (RA), and so CRP is assumed to have a detrimental effect. However, the exact role of CRP in RA remains unknown. To ascertain the contribution of CRP in RA we subjected wild type mice (WT) and CRP deficient mice (moCRP-/-) to collagen-induced arthritis (CIA). To our surprise, disease developed 14 days earlier in moCRP-/- than WT, achieving a threefold higher clinical score. The beneficial effect of CRP in CIA appears to be linked to the protein’s ability to dampen the activation state of dendritic cells (DCs). For example, incubation of bone marrow-derived CD11c+ DCs (BMDCs) with 10 μg/ml purified human CRP reduced display of MHC class II and CD80/86 compared to BMDCs exposed to media alone (8 ± 4% lower and 5 ± 5.5% lower, respectively). This effect was observed whether BMDCs were derived from WT or moCRP-/- but was lost if cells were from mice lacking expression of FcγRIIB, the latter showing increased activation in response to CRP. Based on these observations we suggest that CRP binding to the inhibitory FcγRIIB conveys a signal leading to reduced display of DC activation markers. Accordingly, in the absence of CRP or FcγRIIB this pathway is disrupted, thereby de-inhibiting DCs and rendering moCRP-/- more prone to CIA. Experiments now underway are investigating whether a CRP→FcγRIIB pathway on DCs contributes to maintenance of immune tolerance.
The therapeutic role of resveratrol in allergic lung inflammation (97.2)
Authors: Chen Jing , Lee Sang-Myeong , Fang Deyu , Atasoy Ulus 
Published: January 2023

Abstract
CD4+ T helper type 2 (Th2) cells are crucial for mediating allergic inflammatory lung disease such as asthma, by producing key cytokines including interleukin (IL)-4, IL-5 and IL-13. The phytoalexin, resveratrol, which is rich in grapes and red wine, can increase lifespan and has been suggested as a potential reagent to treat aging-related diseases. Herein we report that resveratrol prevents mice from developing experimental asthma induced by ovalbumin sensitization and re-challenge. Feeding mice with resveratrol inhibits the chronic allergic inflammation in lungs and reduces the numbers of eosinophil/neutrophils in bronchoalveolar lavage fluid. The mechanism appears to be resveratrol-induced suppression of allergic lung inflammation by inhibition of Th2-cytokine production. OVA-specific IL-5 and IL-13 production by CD4+ T cells in treated mice is reduced. Indeed, resveratrol blocks the in vitro polarization of naïve CD4+ T cells to the Th2 phenotype. Western blotting analysis further shows that resveratrol specifically down-regulates the expression of the Th2 transcription factor, GATA-3. These results suggest that resveratrol has therapeutic potential for altering the course of allergic inflammatory lung diseases such as asthma.
Adenosine promotes de novo generation of Th17 Cells via the dendritic cell A2B adenosine receptor (98.7)
Authors: Wilson Jeffrey , Black Steven , Linden Joel , Ernst Peter 
Published: January 2023

Abstract
Differentiation of naïve CD4+ T lymphocytes into appropriate effector subsets is important for generating protective immunity. Factors controlling the development of IL-17 secreting CD4+ T cells (Th17 cells) remain poorly defined. Adenosine is an endogenous metabolite produced during hypoxia or inflammation. Here we report that the stable adenosine mimetic NECA promotes Th17 responses by acting on dendritic cell (DC) adenosine A2B receptor (A2BAR). Culturing highly purified naïve CD4+ T cells with DCs in the presence of NECA results in the differentiation of IL-17 secreting cells and elevation of mRNA encoding signature Th17 molecules such as IL-22 and ROR-γT. Experiments using selective adenosine receptor (AR) antagonists and cells from A2BAR-/- mice indicate that DC A2BAR is largely responsible for the effect. The Th17 induction requires specific cytokine mediators that are selected by NECA-treated DC including IL-6 and TGF-β. PLC and PKC are important intracellular mediators of the A2BAR-mediated IL-6 response, whereas both adenylyl cyclase and PKA are dispensable as evidenced by studies using pharmacologic inhibitors, thus suggesting that A2BAR promotes the Th17 response via a Gq dependent pathway. Hence, in addition to previously noted direct effects of ARs on Treg development and function, these data suggest that under some circumstances adenosine acts via A2BARs expressed on DCs to favor the Th17 lineage.
CD4+ recent thymic emigrants are biased to the Th2 lineage (99.14)
Authors: Hendricks Deborah , Fink Pamela 
Published: January 2023

Abstract
Following intra-thymic development, T cells exit the thymus and join the peripheral T cell pool. These newly generated cells, termed recent thymic emigrants (RTEs), undergo phenotypic and functional maturation for the first 3 weeks they reside in the periphery. Using mice transgenic (Tg) for green fluorescent protein (GFP) driven by the Rag2 promoter (RAG2p-GFP Tg), in which GFP reliably distinguishes RTEs from their more mature naïve (MN) counterparts, our lab is able to isolate untouched RTEs for functional and phenotypic analysis. Activated CD4+ RTEs exhibit defects in IL-2Rα upregulation, proliferation and IL-2 production. We now show that CD4+ RTEs are defective in T helper (Th) 0, Th1, Th17 and regulatory T cell lineage commitment, with dampened cytokine production and transcription factor expression. RTE Th lineage commitment is not globally impaired, however, as CD4+ RTES are biased toward the Th2 lineage, with IL-4, IL-5 and IL-13 production that is enhanced compared to that by identically treated mature T cells. This bias in RTEs likely results from dampened negative regulation of the Th2 lineage by diminished levels of T-bet, a key Th1 transcription factor. CD4+ RTEs are thus a transitional population defined by their distinct interpretation of, and response to, immunological cues. These characteristics may be beneficial during the post-thymic maturation period to avoid inappropriate immune responses, particularly in lymphopenic neonates and adults.
Antigen-specific Th9 cell lines exhibit unique features (99.2)
Authors: Tan Cuiyan , Vistica Barbara , Shi Guangpu , Aziz Mehak , Gery Igal 
Published: January 2023

Abstract
Research in recent years has shown that naïve lymphocytes can differentiate into lineages (Th1, Th2, Th17 and Treg cells) with distinct effector functions and signature cytokines. Two recent publications reported the generation of Th cell lines that specifically express high levels of IL-9 and IL-10 and were designated “Th9”. These lines were generated by activation of naïve lymphocytes with antibodies against CD3/CD28, in the presence of the polarizing cytokines IL-4 and TGF-β. Here, we analyzed features of “Th9” cells generated by activation with the specific antigen. T-cells transgenically expressing T-cell receptor (TCR) specific to hen egg lysozyme (HEL) were activated with this antigen in the presence of the polarizing cytokines IL-4 and TGF-β. Main observations: (i) IL-9 and IL-10 were expressed with remarkably different kinetics; (ii) re-activation of “Th9”, following expansion, triggered faster and higher production of both IL-9 and IL-10; (iii) incubating “Th9” cells in polarizing media of other phenotypes stimulated low levels of phenotype switching to Th1 or Th17, but a massive switching to Th2; (iv) “Th9” induced moderate inflammation in HEL expressing recipient eyes, but only when collected at stages at which IL-9 was produced. Thus, “Th9” cells exhibit unique features that differentiate them from other known Th lines.
T Cell Factor-1 Initiates T Helper 2 Fate by Inducing GATA-3 and Repressing IFNgamma (99.8)
Authors: Yu Qing , Sharma Archna , Sen Jyoti 
Published: January 2023

Abstract
Differentiation of activated CD4 T cells into T helper (Th) -1 and -2 cell fate is regulated by cytokines and transcription factors T-bet and GATA-3. Whereas it is clear that IL-12 produced by antigen presenting cells initiate Th1 fate, signals that initiate Th2 fate have not been completely characterized. Here we show that Gata-3, an essential transcription factor for Th2 differentiation, is initially induced by T cell factor-1 (TCF-1) and its cofactor beta-catenin, predominantly from the proximal promoter upstream of exon 1b. This activity is induced in CD4 T cells early after T cell receptor stimulation and is independent of IL-4 receptor signaling via STAT-6. Furthermore, we show that TCF-1 blocks Th1 fate by negatively regulating IFNgamma expression, independently of beta-catenin. Thus, our results indicate that TCF1 initiates Th2 differentiation of activated CD4 T cells by a dual mechanism: by promoting Gata-3 expression and suppressing IFNgamma expression.
Human T follicular helper cells comprise subsets specialized for help of distinct B cell subsets (99.9)
Authors: Bentebibel Salah-Eddine , Schmitt1 Nathalie , Morita Rimpei , Banchereau Jacques , Ueno Hideki 
Published: January 2023

Abstract
T follicular helper cells (Tfh) represent a Th subset specialized for the help of antibody responses. In contrast to recent progress regarding the phenotype and developmental mechanism of Tfh cells, how Tfh cells regulate B cell responses is less well characterized. In particular, whether Tfh cells are involved in the differentiation of naïve B cells into antibody-secreting cells (ASCs) remains largely unknown. Here we show that human tonsillar Tfh cells comprise subsets specialized for the help of distinct B cell subsets. A subset of Tfh cells, here called Pre-Tfh cells, is specialized for the help of naïve B cells. In contrast, Tfh cells at germinal centers (GC-Tfh cells) are the only Tfh subset able to induce germinal center B (GC-B) cells to produce Igs. Despite the capacity to secrete high levels of Interleukin-21 (IL-21), Pre-Tfh cells failed to help GC-B cells, due to the induction of apoptosis of GC-B cells via FAS/FAS ligand interaction. While Pre-Tfh cells were found exclusively at extrafollicular sites, Pre-Tfh cells expressed Bcl6, a master transcription factor of Tfh cells, at equivalent levels with GC-Tfh cells. A comprehensive gene expression profiling strongly suggests that pre-Tfh cells are progenitors of GC-Tfh cells. Thus, the differentiation of functional human Tfh cells already occurs at outside of B cell follicles, and such extrafollicular Tfh cells are engaged in the differentiation of naïve B cells.
Non-covalent interaction of Abacavir with HLA-B*5701 generates an antigenic complex recognized by specific T cells (100.13)
Authors: Adam Jacqueline , Eriksson Klara , Schnyder Benno , Fontana Stefano , Pichler Werner , Yerly Daniel 
Published: January 2023

Abstract
Rationale: Abacavir (ABC) hypersensitivity is mediated by specific CD8+ T cells that interact with ABC in HLA-B*5701+ individuals. To understand how ABC is presented and recognized by T cells, we generated ABC specific T cell clones (ABC-TCC) and analysed the kinetic of ABC recognition. Methods: ABC-TCC from ABC naïve HLA-B*5701+ subjects were generated by limiting dilution. TCC activation by ABC was measured by means of Ca2+ influx kinetic analyses and Annexin V staining. Results: ABC-TCC in presence of autologous antigen-presenting cells (APC) reacted within a short time (3-25 min) to ABC in solution. Interestingly, APC that internalized the drug were able to present it already after 30 min on the cell surface leading to an immediate TCC activation (60 sec). Furthermore, no mRNA for alcoholdehydrogenases (ADH), the enzymes involved in ABC metabolism, was detected in the immune cells of peripheral blood. Conclusions: The rapid kinetic of TCC reactivity to ABC presented by HLA-B*5701 and the lack of ADH activity in peripheral blood mononuclear cells is best explained by a direct, metabolism and processing independent interaction of ABC with the restricting HLA-B*5701 molecule. This interaction either occurs intracellular or on the cell surface, leading to a modification of the HLA-complex able to induce a full T cell response. Our data underline that the immune stimulatory capacity of drugs is not uniquely restricted to the ability to form covalent bonds to proteins.
TAP-independent presentation of the melanoma vaccine candidate epitope gp100209-217 requires no gp100 sequences outside the core peptide and is sensitive to cytosolic TPP2 degradation (100.2)
Authors: Leonhardt Ralf , Vigneron Nathalie , Van den Eynde Benoît , Cresswell Peter 
Published: January 2023

Abstract
gp100209-217 is a promising anti-melanoma peptide vaccine that corresponds to an immunodominant, HLA-A*0201-restricted tumor-epitope. As an immune evasion strategy many tumors display downregulation or even total lack of expression of the TAP transporter, a crucial factor involved in MHC class I-mediated antigen presentation. Surprisingly, we find that HLA-A*0201-mediated presentation of gp100209-217 is remarkably independent of TAP and thus the peptide likely uses an unconventional pathway to access MHC class I molecules. Our data suggest that presentation does not involve proteolysis in one of the diverse protease-rich compartments that gp100 traverses on its way to melanosomes. Neither is melanosomal targeting or ER-export of gp100 required, nor is even co-translational insertion of the protein into the ER membrane necessary. However, presentation of the epitope does depend on proteasome activity. Interestingly, we find that cytosolic tripeptidyl peptidase 2 (TPP2) efficiently counteracts TAP-independent presentation of gp100209-217 suggesting that tumors might use this protease for immune evasion. Strikingly, no sequences outside the core peptide region within gp100 are required for TAP-independent access of the ligand to HLA-A*0201. We conclude that a transporter system besides TAP must exist in the cell, which can partially compensate for loss of TAP function and mediate access of critical tumor-specific antigenic peptides to HLA-A*0201.
An insertion mutant in DQA*0501 restores susceptibility to DM: implications for disease associations (100.22)
Authors: Hou Tieying , Macmillan Henriette , Strohman Michael , Yoon Taejin , Jin Xi , Mellins Elizabeth 
Published: January 2023

Abstract
HLA-DM (DM) catalyzes CLIP release, stabilizes MHC class II molecules and edits the peptide repertoire presented by class II. Impaired DM function may have profound effects on antigen presentation events in the thymus and periphery that are critical for maintenance of self-tolerance. The associations of the HLA-DQ2 (DQ2) with autoimmune diseases, like celiac disease, have been appreciated for a long time. The explanation for these associations, however, remains unknown. We previously found that DQ2 is a poor substrate for DM. Here, to further characterize DQ2-DM interaction, we introduced point mutations into DQ2 on the proposed DQ2/DM interface in order to restore the sensitivity of DQ2 to DM. The effects of mutations were investigated by measuring the peptide dissociation and exchange rate in vitro, CLIP and DQ2 expression on cell surface and the presentation of α-gliadin 57-73 Q65E epitope to T cell hybridomas. We found that the three α chain mutations (α+53G, α+53R and αY22F) decreased the intrinsic stability of peptide-class II complex. More interestingly, the α+53G mutant restored DQ2 sensitivity to DM, likely due to improved interaction with DM. Our data also suggest that α-gliadin 57-73 is a DM-suppressed epitope. The DQ2 resistance to DM changes the fate of this peptide from a cryptic to an immunodominant epitope. Our findings elucidate the structural basis for reduced DQ2-DM interaction and have implications for mechanisms underlying disease associations of DQ2.
Efficient lipid antigen presentation to NKT cells by targeting CD169/Siglec-1 on macrophages with its glycan ligand. (100.49)
Authors: Kawasaki Norihito , Chen Weihsu , Vela Jose , Nycholat Corwin , Maricic Igor , Vipin Kumar , Crocker Paul , Kronenberg Mitchell , Paulson James 
Published: January 2023

Abstract
Natural killer T (NKT) cells are a subset of T cells expressing an invariant TCR with cross-species conserved specificity to glycolipid antigens in the CD1d restricted presentation. Recent studies have identified CD169/Siglec-1+ macrophages as antigen presenting cells for NKT cells. Here we show that delivery of the lipid antigen through CD169 on macrophages induces NKT cell activation. We developed CD169-targeted liposomes decorated with a specific glycan ligand of CD169 (9-N-biphenylcarboxyl-NeuAcα2-3Galβ1-4GlcNAc) and observed that CD169-targeted liposomes were captured by macrophages in the CD169-dependent manner, and delivered to lysosomes, the known site of lipid antigen loading on CD1d. We next investigated the ability of the CD169-targeted liposomes to promote NKT cell activation by delivery of a lipid antigen α-GalCer to macrophages. We found that macrophages pulsed with α-GalCer containing CD169-targeted liposomes efficiently presented the lipid antigen to NKT cells when transferred into the C57BL/6J mouse. Alternatively, intravenous injection of the α-GalCer containing CD169-targeted liposomes activated NKT cells 100-fold more efficiently than lipid antigen alone in vivo. CD169-targeted liposomes without α-GalCer did not activate NKT cells, demonstrating this activation is through cognate antigen recognition by NKT cells. These data demonstrate that CD169-targeted liposomes dramatically enhance lipid antigen delivery to macrophages for NKT cell activation in vivo.
Essential glycan-dependent interactions optimize MHC class I peptide loading (100.51)
Authors: Wearsch Pamela , Zhang Wei , Cresswell Peter 
Published: January 2023

Abstract
In this study we sought to better understand the role of the glycoprotein quality control machinery in the assembly of MHC (Major Histocompatibility Complex) class I molecules with high-affinity peptides. The lectin-like chaperone calreticulin (CRT) and the thiol oxidoreductase ERp57 participate in the final step of this process as part of the PLC (peptide-loading complex). To investigate the mechanism of peptide loading and roles of individual components, we reconstituted a PLC sub-complex, excluding TAP, from purified, recombinant proteins. The minimal components required for PLC assembly and function in vitro were ERp57 disulfide-linked to the class I-specific chaperone tapasin, CRT, and MHC class I complexes bearing monoglucosylated glycans. Mutations disrupting the interaction of CRT with either ERp57 or the class I glycan completely eliminated tapasin-mediated peptide loading. Using the purified system, we also provide direct evidence for a novel role of UGT1 (UDP-glucose: glycoprotein glucosyltransferase 1) in MHC class I assembly. Recombinant UGT1 preferentially recognized and re-glucosylated class I molecules associated with a suboptimal ligand and allowed PLC re-engagement and peptide exchange. Collectively, the data indicate that the interaction of MHC class I molecules with the PLC is regulated by its N-linked glycan, and that UGT1 contributes to the optimization of the MHC class I peptide repertoire in addition to tapasin.