bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activated IL-1R1 Signaling Pathway Induces Th17 Cell Differentiation in Patients with Relapsing Remitting Multiple Sclerosis (83.18)
Authors: Sha Yonggang , Troiani Luigi , Chopra Manisha , Markovic-Plese Silva 
Published: January 2023

Abstract
BACKGROUND: IL-1β plays a crucial role in the development of human Th17 cells. However, its mechanisms of action are still not completely elucidated. Recent has study discovered that Th17 cells are characterized by IL-1R1 expression. RESULTS: Our study has revealed that IL-1R1 and IL-1R2 gene expression is significantly increased in both naïve and memory CD4+ T-cells derived from patients with relapsing-remitting multiple sclerosis (RRMS) in comparison to matched healthy controls. IL-1R1 expression is up-regulated in the in vitro differentiated Th17 cells in comparison to the Th1 and Th2 cell subsets. IL-17A production was induced by IL-1β. This induction was blocked by IL-1R antagonist in the naïve CD4+cells cultured in the presence of Th17 polarizing cytokines. When IL-1R1 gene expression was silenced using siRNA, human naïve CD4+ T-cells cultured in the presence of Th17 polarizing cytokines had a significantly decreased expression of IL-21, IL-22, IL-23R, IRF4, RORC, IL-17A and IL-17F genes, confirming that IL-1R1 signaling induces Th17 cell differentiation. IRF4 gene expression silencing, similarly inhibited Th17 cell differentiation in the presence of IL-1b, indicating that IL-1R1 signals upstream of IRF4. CONCLUSION: Our study has identified that IL-1R1-mediated signaling pathway may be constitutively activated, leading to an increased Th17 cell expansion and autoimmune response in patients with RR MS.
CD44act as a marker for T cell regulatory activity in inflammatory bowel disease (83.21)
Authors: Estess Pila , Shah Rajesh , Siegelman Mark 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD) is an autoimmune condition that results from attack of intestinal tissue by effector T cells. While CD4+CD25+ naturally occurring regulatory T cells (Treg) have great potential for treatment of IBD and other autoimmune conditions, therapeutic use is hindered by the inability to identify those most specific for controlling disease and difficulty in distinguishing them from T effector cells that induce disease. We have investigated the isolation of highly competent Treg from patients with Crohn’s Disease and Ulcerative Colitis using the conformationally activated hyaluronan-binding form of CD44 (CD44act), previously shown to be associated with markedly improved Treg function and traffic to sites of inflammation. Using a CD44act-dependent primary adhesion assay, we have demonstrated that this marker can be used to reliably identify and isolate functional regulatory T cells from PBMC of affected individuals. Among IBD patients, greater numbers of circulating T lymphocytes bearing CD44act are found in peripheral blood during disease flare or during resolution of disease flare, consistent with a regulatory role. Isolated CD44act T cells from patient blood prevent the activation of Teffector cells from the same individual. After isolation and in vitro expansion, these cells retain regulatory behavior and express cytokines consistent with their being regulatory T cells
Resting B cells as Inducers of Antigen-Specific T Regulatory Cells (83.22)
Authors: Zhai Yougang , Zhou Lan , Zhong Zhenyu , Qiao Liang 
Published: January 2023

Abstract
We have previously shown that resting B cells are able to expand T regulatory cells through TGF-beta3 whereas activated B cells induce increased apoptosis of T regulatory cells. Thus, we hypothesize that resting B cells can be used to induce antigen-specific T regulatory cells. To test our hypothesis, we isolate resting B cells from mice and load the cells with Ova, and then adoptively transfer the B cells to Ova-specific TCR transgenic mice. We determine numbers of OVA-specific T effector cells and T regulatory cells in the adoptively transferred mice and in control mice that receive untreated resting B cells alone by flow cytometry (Foxp3). We further determine if these T regulatory cells mediate immunosuppressive activities by using proliferation assay in vitro and by in vivo prevention of immune response against challenge with OVA + adjuvant. This study will provide basis to develop approaches to induce antigen-specific T regulatory cells to treat inflammatory diseases such as allergy and autoimmune diseases.
Induction of antigen specific T regulatory cells to suppress inflammatory responses by tolerogenic vaccination (83.6)
Authors: Wang Bin , Jin Jin 
Published: January 2023

Abstract
Inflammatory disorders, such as asthma, could be detrimental. Dust mites may cause 50-80% of asthma cases. No effective treatments, particularly those targeted to antigen-specific inhibition, are still lacking. In our previous study demonstrated that co-immunization of DNA and protein vaccines together as tolerogenic vaccination into animal could inhibit inflammatory responses in a antigen-specific matter. Using dust mite induced asthma as model, we assess the immunotelarogenic effect of co-immunization. Mice immunized with a Derp1 tolerogenic vaccine were examined their ability to prevent this experimental asthma by assessment of infiltrations of eosinophils and lymphocytes into lungs. The immunization with the tolerogenic antigens not only induced significant decrease of inflammatory responses in the lungs, but also to inhibit Th2 cytokines and production of IgE. The induced tolerogenic responses are associated tightly with the generation of CD4+CD25-Foxp3+ iTregs. We observe that these iTregs exhibit phenotypic markers including IL10+, CTLA4low, GITRlow, PD-1- and ICOSlow, which differ from those documented natural CD4+CD25+ Tregs and iTreg. Blockade of TGF-β1 could demolish the induction of this iTregs and suppressive responses. This tolerogenic vaccination induces the iTreg via TGF-β1 and present a novel therapeutic strategy to treat or prevent inflammatory disorder related diseases.
Computational modeling of B cell signaling shows B cell affinity discrimination requires kinetic proofreading (84.2)
Authors: Tsourkas Philippos , Raychaudhuri Subhadip 
Published: January 2023

Abstract
B cells signaling in response to antigen is proportional to antigen affinity, a process known as affinity discrimination. B cells can acquire antigen in membrane-bound form on the surface of antigen-presenting cells (APCs), with signaling being initiated within a few seconds of contact. During the early stages of contact, B cell receptors (BCRs) on protrusions of the B cell surface bind to antigen on the APC surface and form micro-clusters of 10-100 BCR-antigen complexes. We use a Monte Carlo computational model to show that B cell affinity discrimination at the level of micro-clusters requires a threshold antigen binding time, similar to kinetic proofreading. We find that if BCR molecules become signaling-capable immediately upon binding antigen, there is a loss in serial engagement as BCR-antigen affinity increases, due to the increased bond lifetime of high-affinity bonds. This results in an unnatural decrease in signaling strength with increasing affinity. A threshold antigen binding time favors high affinity BCR-antigen bonds, as these long-lived bonds can better fulfill the threshold time requirement than low-affinity bonds. A threshold antigen binding time of ~10 seconds results in monotonically increasing signaling with affinity, as seen in B cell activation experiments. This time matches well with the experimentally observed time (~20 seconds) of lipid raft-mediated conformational changes in BCR signaling domains that lead to association with Syk.
BCR mediated c-Rel induction facilitates NF-κB2 and RelB expression (84.22)
Authors: Wright Jacqueline , Castro Iris , Damdinsuren Bazarragchaa , Hoek Kristen , Carlesso Gianluca , Shinners Nicholas , Gerstein Rachel , Woodland Robert , Sen Ranjan , Khan Wasif 
Published: January 2023

Abstract
B cell receptor (BCR) and B cell activating factor receptor (BAFF-R) signaling are critical for the generation of mature splenic B cells. BCR expressing Transitional type 1 (T1) cells migrate from the bone marrow to the spleen where they must successfully pass BCR mediated checkpoints to become Transitional type 2 (T2) cells and subsequently mature follicular B (FoB) cells. T1 and T2 cells are fundamentally different in their response to BCR or BAFF-R stimulation; T1 cells do not survive whereas T2 cells do when triggered through BCR or BAFF-R. Our results demonstrate that Bruton’s tyrosine kinase (Btk) plays a critical role in both BCR and BAFF-R mediated T2 and mature B cell survival. These results suggest that a potential mechanism that provides T2 cells with a survival advantage is their ability to sustain c-Rel expression in response to BCR engagement via mechanisms involving Btk. The increased c-Rel expression coincides precisely with the up-regulation of anti-apoptotic members of the Bcl-2 family as well as BAFF-R and its substrate p100 (NF-κB2). Thus, BCR indirectly enhances the survival function of BAFF-R in part through c-Rel. Consistent with a supporting role for BCR/c-Rel signaling in the activation of alternative NF-κB pathway, c-Rel-deficient B cells are impaired for BCR-induced expression of p100 as well as RelB.
CD40 signaling regulates both adaptive and innate immune receptors through TRAF degradation (84.3)
Authors: Graham John , Bishop Gail 
Published: January 2023

Abstract
CD40, a tumor necrosis family member, is a costimulatory molecule central to adaptive immune responses. CD40 activates many of the same pathways as innate immune receptors; however, the outcome of CD40 signaling is much different. Whereas innate immune receptors rapidly initiate early protective immune responses, CD40 engagement and signaling results in a fundamental change toward a regulated, adaptive immune response. The specific regulatory signals that restrain the CD40 response have remained elusive. Here we show that upon signaling, CD40 specifically negatively regulates its own signals as well as those delivered by other receptors that rely on TRAF2 and TRAF3 for signaling. This negative regulation of CD40 and TLR signals is caused by CD40’s unique ability to induce both TRAF2 and TRAF3 degradation upon signaling. Hence CD40, as a molecule central to immune responses, is not only able to regulate its own signals, it is able to transition an immune response from an early inflammatory stage to a regulated adaptive stage.
Fc receptor-like 5 has dominant inhibitory function in B cells that is mediated via Lyn and SHP-1 (84.5)
Authors: Zhu Zilu , Davis Randall 
Published: January 2023

Abstract
An extended family of Fc receptor-like (FCRL) molecules has tyrosine-based signaling properties and is preferentially expressed by B lineage cells. In mice, FCRL5 is distinguished by its discrete expression among innate B lineage lymphocytes including splenic marginal zone B cells and peritoneal cavity-derived B1 B cells. FCRL5 has five Ig-like extracellular domains and a cytoplasmic tail containing an ITAM-like sequence and a consensus ITIM. To evaluate its signaling functionality, chimeric receptors comprised of the extracellular and transmembrane portions of FcγRIIb in frame with cytoplasmic Y&gt;F variants of FCRL5 were generated in the mouse A20-IIA1.6 B cell line. Pervanadate treatment of chimeric transductants revealed that both tyrosine-based motifs can be phosphorylated. Coligation of the unmodified FcγRIIb/FCRL5 chimeric receptor with the B cell receptor (BCR) inhibited calcium mobilization, whole cell tyrosine phosphorylation, and Erk kinase activation via the ITIM-dependent (Y566) recruitment of the SHP-1 phosphatase. Conversely, coligation of a chimeric mutant bearing the intact ITAM-like (Y543/Y556) sequence with the BCR resulted in subtle but consistent enhancement of calcium mobilization. This activation effect correlated with the recruitment of the Src-family kinase, Lyn. The inhibitory influence of FCRL5 was similarly observed in primary splenic marginal zone B cells. These data indicate that FCRL5 serves as a dominant inhibitory co-receptor in B cells.
Pax5 and E47 regulate AID and class switch recombination in young and aged BALB/c mice (84.6)
Authors: Landin Ana Marie , Frasca Daniela , Harrison Patrick , Scallan Martina , Hagman James , Blomberg Bonnie 
Published: January 2023

Abstract
Our laboratory has shown that stimulated B cells from senescent mice (19 to 24 months) have an intrinsic defect in class switch recombination (CSR) that is coincident with reduced E47. In aging, the decrease in E47 correlates proportionally with levels of activation induced cytidine deaminase (Aicda/AID) transcripts; but, other transcription factors may be involved. Pax5 has been shown to play a role in CSR. The purpose of the present study was to determine whether 1) Pax5 is decreased with age, 2) the decrease in Pax5 correlates with decreased CSR in aged B cells, 3) increased E47 and/or Pax5 can rescue the decreased CSR observed in these cells and 4) depletion of Pax5 down-regulates E47 and/or AID expression. Here, we demonstrate that E47 and Pax5 are both down-regulated in mature splenic B cells of aged mice. Endogenous E47, Pax5 and IgG1 are increased in old as well as young primary stimulated B cells in response to exogenously expressed E47. We successfully rescued levels of both E47 and Pax5 mRNA and protein in transduced splenic B cells of aged mice when compared to young untransduced controls. Restoration of Pax5 expression increased E47, AID and CSR in B cells from aged mice. Conversely, silencing Pax5 by means of siRNA transfection decreased E47 and AID expression significantly. These results suggest a possible feedback mechanism between E47 and Pax5. Our results show that E47 and Pax5 cooperate to regulate AID and CSR in both young and old B lymphocytes.
MS4a4B, a CD20 Homologue in T cells, inhibits T cell propagation by modulation of cell cycle (85.1)
Authors: Xu Hui , Yan Yaping , Williams Mark , Carey Gregory , Yang Jingxian , Li Hongmei , Zhang Guang-Xian , Rostami Abdolmohamad 
Published: January 2023

Abstract
MS4a4B, a homologue of CD20 in T cells, is a novel member of the MS4A gene family (Membrane-spanning 4-domain family, subfamily A). Recent data showed that MS4a4B may play functional roles in regulation of Th1 and regulatory T cells. We have demonstrated previously that MS4a4B negatively regulates T cell proliferation. Over-expression of MS4a4B in primary T cells and EL4 thymoma cells by viral vector inhibits cell proliferation. In this study, we determined whether MS4a4B inhibited T cell proliferation by modulating cell cycle progression. We transfected EL4 cells with either MS4a4B or mock lentiviral vectors and isolated stably transfected cells by flow cytometry. Transfected EL4 cells were synchronized by serum starvation and thymidine treatment, and then were stimulated with complete medium containing 15% fetal calf serum. We found that overexpression of MS4a4B in EL4 cells interfered with cell cycle progression from G0/G1 to S-G2/M phase. To further confirm the role of MS4a4B in cell cycle regulation, we knocked down expression of MS4a4B in T32 cells, a MS4a4B+ T cell line, by shMS4a4B-lentiviral vector. The results showed that shMS4a4B-mediated reduction of MS4a4B expression promoted cell cycle progression. Our data suggest that MS4a4B inhibits T cell proliferation by suppression of cell cycle progression. Supported by American Heart Association grant AHA-0830072N (to H.X)
Localization of Fas/CD95 to lipid raft microdomains sensitizes human CD4+ effector memory T cells to Fas-induced apoptosis (85.13)
Authors: Cruz Anthony , Ramaswamy Madhu , Siegel Richard 
Published: January 2023

Abstract
Fas-FasL interactions play a critical role in TCR-induced apoptosis of activated CD4+ T cells. However, naïve T cells activated through acute antigen stimulation expand and contract independently of the presence of the death receptor Fas. Fas deficiency prompts the accumulation of CD44+ memory phenotype T cells and autoimmunity in mice, suggesting Fas may play a critical role in memory and/or autoreactive T cell apoptosis. We have previously shown a correlation between lipid raft-associated Fas and sensitivity to apoptosis. Whether or not lipid raft microdomains influence Fas signaling in primary T cells, and whether lipid raft association of Fas is regulated in different primary cell types is unknown. Therefore, we have compared the sensitivity of purified naïve versus memory human CD4+ T cells to undergo Fas-mediated apoptosis. Effector memory phenotype cells lacking both the chemokine receptor CCR7 and the TNFSFR CD27 were the most sensitive to both anti-Fas antibody as well as FasL-induced cell death. Memory T cells have increased lipid raft-associated Fas receptor versus naïve cells, which could explain the increased Fas sensitivity in the memory pool. Using a competitive inhibitor to palmitoylation, we found sensitivity of effector memory T cells to Fas-induced apoptosis depended on Fas palmitoylation. These results suggest that effector memory cells are intrinsically more sensitive to Fas-induced apoptosis, possibly due to lipid raft localization of Fas.
Bim regulates the entry of poorly functional and/or low avidity Th1 effector cells into the memory pool (85.15)
Authors: Williams Matthew , Jay David 
Published: January 2023

Abstract
Following the clearance of acute infection, most pathogen-specific effector T cells die, with a small minority (5-10%) surviving the contraction phase and populating the memory T cell compartment. The pro-apoptotic Bcl-2 family member Bim is central in eliminating end-stage effector T cells during contraction. We recently found that not all clones that populate the effector Th1 pool are represented in the memory phase, and failure to survive corresponded to low TCR structural and functional avidity as well as increased Bim expression. We hypothesized that Bim was required to remove unwanted low avidity Th1 responders during the transition from effector to memory. We found that Bim-deficiency rescued the survival of end-stage Th1 effector clones and allowed their entry into the memory pool. However, these cells displayed decreased primary effector function and poor recall capacity, demonstrating that while Bim played a T cell intrinsic role in the death of Th1 effector cells, its absence did not permit the rescue of effector or memory Th1 cell function. Additionally, Bim-deficient CD4+ memory T cells declined at a rate similar to wildtype memory cells, suggesting that their survival is regulated by Bim-independent factors. We propose that Bim plays a crucial role in shaping optimally functional CD4+ memory T cell repertoires by removing low avidity and/or poorly functional Th1 clones during contraction.
Two distinct functions for the BTB domain of the CD4-differentiating factor Thpok (85.20)
Authors: Zamisch Monica , Wang Lie , Yockey Laura , Vinson Charles , Bosselut Remy 
Published: January 2023

Abstract
Thpok is a zinc-finger (ZF) transcription factor essential for CD4 T cell development. Thpok promotes CD4 T helper lineage commitment, in part through the repression of genes necessary for CD8 differentiation. A member of the BTB-ZF subclass of ZF transcription factors, Thpok contains two conserved motifs: a carboxy-terminal ZF DNA binding domain, and an amino-terminal BTB motif. Although the BTB domain is required for Thpok to promote CD4 lineage differentiation, its contribution to Thpok function is not clear. In vitro analyses of the BTB domain of the prototype family member, Bcl6 (B cell lymphoma 6) revealed a role of the BTB domain in oligomerization and transcriptional repression. In the present study, we examined whether the Thpok BTB domain simply serves to promote dimerization of Thpok molecules, or whether it also serves to recruit other transcriptional regulators. We generated chimeric Thpok proteins by replacing the BTB domain of Thpok with that of other family members, or with a heterologous dimerization domain. All chimeric molecules containing the BTB domains tested blocked CD8 lineage specific gene expression; in contrast, the chimeric molecule carrying a heterologous dimerization domain was only partially functional. These results indicate that the BTB domain of Thpok not only promotes dimerization but it also serves to control transcription, presumably through interactions with transcriptional corepressors.
WOX1 and MEK1 interactions determine T cell sensitivity to PMA-mediated apoptosis (85.4)
Authors: Chang Nan-Shan , Lin Hsin-Ping , Hsu Li-Jin 
Published: January 2023

Abstract
Phorbol myristate acetate (PMA) mimicks the function of diacylglycerol in binding to PKC and activating downstream Ras/Raf/MEK/ERK pathway. Here, we determined that PMA, at μM levels, rapidly induced ERK phosphorylation and WOX1 expression in less than 30 min, and subsequent apoptosis in 24 hr in Jurkat T cells (determined by DNA fragmentation and cell cycle analysis). WOX1, also named WWOX or FOR, is a tumor suppressor and a proapoptotic protein. In resting cells, WOX1 is present in the cytoplasm. When these cells were pretreated with a MEK inhibitor U0126 or overexpressed with dominant-negative WOX1, PMA-induced cell death was blocked. In stark contrast, less differentiated Molt-4 T cells were refractory to PMA-induced apoptosis. Most intriguingly, U0126 dramatically reduced the resistance and rendered apoptosis in Molt-4 T cells. Induction of Molt-4 T cell differentiation by nanomolar PMA restored its sensitivity to micromolar PMA-induced apoptosis. By co-immunoprecipitation and FRET, WOX1 was shown to physically interact with MEK1 in Jurkat T cells. PMA rapidly induced the dissociation of the WOX1/MEK1 complexes and U0126 blocked the dissociation, thereby supporting cell survival. Together, we described a novel PMA signaling to induce dissociation of the cytosolic WOX1/MEK1 complexes, thereby allowing WOX1 nuclear relocation for inducing apoptosis.
Selective loss of dominant low affinity CD4 T cells during memory differentiation (85.6)
Authors: Baumgartner Christina , Malherbe Laurent 
Published: January 2023

Abstract
Antigen-specific memory T cells are crucial for conveying protection against pathogens upon vaccination. The evolution of the CD4 memory T cell repertoire is not fully understood. We analyzed CD4 memory T cell differentiation of a diverse, private and broad affinity CD4 T cell repertoire that developed in draining lymph nodes of mice 7 days after immunization with moth cytochrome c peptide (MCC88-103) in MPL-based adjuvant. 30 days after primary immunization we found a dramatic remodeling of the repertoire. The initially diverse repertoire evolved into a focused and public repertoire expressing high affinity T cell receptors. Importantly, 30 days after primary immunization we observed a selective loss of one particular low affinity clonotype that dominated the primary response at day 7. Absence of this clonotype in draining lymph nodes was not due to recirculation through the animal, since we could not detect this clonotype after re-challenge of mice with the peptide 30 days after primary immunization. Additionally, when we immunized mice with yet another peptide of high peptide-MHCII stability we observed a dramatic repertoire focusing towards high affinity clonotypes to the same extent as in MCC88-103 immunized mice. Thus, after primary immunization only public, high affinity CD4 T cells differentiate into memory CD4 T cells.