bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitamin B1 is an essential survival factor for naïve B cells but not IgA-secreting plasma cells (120.9)
Authors: Wake Taichi , Kunisawa Jun , Hashimoto Eri , Suzuki Yuji , Kiyono Hiroshi 
Published: January 2023

Abstract
It is generally accepted that dietary factors contribute in the regulation of various immunological functions. Among different kinds of dietary materials, vitamin families such as vitamin A, B6, B9, and D3 play critical regulatory roles for immune responses, but the immunological functions of the other vitamins remain largely unknown. Here, we demonstrate that vitamin B1, also known as thiamine, is an essential factor to keep naïve B cells but not IgA-secreting plasma cells. When mice were maintained with vitamin B1-deficient diet, IgM+ B220+ naïve B cells were significantly decreased in the spleen, mesenteric lymph nodes, and Peyer’s patches, while B220- CD138+ plasma cells secreting IgA antibodies were normally present in the small intestine. In agreement with this finding, despite the reduction of naïve B cells, levels of antigen-specific intestinal IgA responses were unchanged in mice receiving vitamin B1(-) diet after oral immunization with Choleratoxin. Similarly, IgA-secreting cells normally produced IgA even in the absence of vitamin B1 in vitro. These findings demonstrate a new immunological function of vitamin B1 at the different B cell stages.
ZEB2 plays a role in promoting T-bet expression and terminal differentiation of CD8+ T cells (121.10)
Authors: Dominguez Claudia 
Published: January 2023

Abstract
We are interested in deciphering the transcriptional programs that underlie the differentiation of the effector CD8 T cell response. Prior work has shown T-bet operates in a gradient fashion, with higher T-bet expression being critical for the development of terminal effector (TE) CD8 T cells. Expression profiling revealed that T-bet regulates ZEB2, a transcriptional repressor that is expressed 10 fold higher in TE cells compared to memory precursor (MP) effector CD8 T cells. To further investigate what role ZEB2 might play in promoting terminal differentiation of CD8 T cells we conditionally knocked out ZEB2 in activated CD8 T cells using Granzyme B Cre ZEB2 flox/flox mice (ZEB2 KO). Upon infection with LCMV, the CD8 T cell expansion in the ZEB2 KO was about half that of wild type mice. The ZEB2 KO CD8 T cells showed an accelerated maturation of the effector CD8 T cell compartment to a memory phenotype with increased IL-2 production and the acquisition of CD62L. Further analysis revealed that these phenotypes might be largely due to the reduction of the TE subset. In the absence of ZEB2, TE CD8 T cells adopt some MP characteristics such as CD27, CXCR3, and Eomes but reduced T-bet and Blimp-1. Our observations suggest that ZEB2 is critical for the maintenance of the transcriptional program that drives terminal differentiation including T-bet. Hence, we propose that ZEB2 and T-bet operate in a positive-feedback mechanism to drive CD8 T cells towards terminal differentiation.
Transcriptional regulator Id2 is required for the CD4 T cell immune response in the development of experimental autoimmune encephalomyelitis (121.12)
Authors: Lin Yen-Yu , Jones-Mason Mary , Inoue Makoto , Iavarone Antonio , Lasorella Anna , Shinohara Mari , Zhuang Yuan 
Published: January 2023

Abstract
Inhibitor of DNA binding 2 (Id2) is an important transcription regulator in lymphocytes. By forming heterodimers with E proteins, Id2 can inhibit E protein-mediated gene regulation, which is critical in controlling many steps of lymphocyte development. However, its role in mature CD4 T cell function is not well-characterized. Here we show that Id2 expression is higher in activated CD4 T cells. Utilizing a T cell-specific conditional Id2 knock-out mouse model, we find that Id2 is essential for the development of experimental autoimmune encephalomyelitis (EAE). Id2-deficient CD4 T cells fail to infiltrate the central nervous system, form a smaller pool of effector cells in the peripheral lymphoid organs and have increased cell death. These CD4 T cells express higher levels of Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of T cell response and a potential target of E proteins. This is the first evidence showing an indispensible role of Id2 in the development of a Th17-mediated autoimmune disease.
Severe sepsis results in modulated chromatin modifying enzyme expression in bone marrow resident hematopoietic stem cells (121.15)
Authors: Carson William , Takahashi Sakuma , Allen Ronald , Kunkel Steven 
Published: January 2023

Abstract
Uncontrolled inflammatory responses drive the high mortality observed in severe sepsis and septic shock. Paradoxically, survivors of severe sepsis exhibit profound cellular immunosuppression, resulting in increased susceptibility to secondary, opportunistic and nosocomial infections. Recent studies have identified epigenetic repression of genes in peripheral immune cells post-sepsis as one possible mechanism underlying this immunosuppression. As post-septic immunosuppression can manifest long after recovery from sepsis, it was hypothesized that any observed epigenetic regulation of pro-inflammatory genes may also occur in hematopoietic stem cells, and in turn, these changes would be due to the up- or down-regulation of chromatin modifying enzymes (CMEs). Superarray analysis of mRNA isolated from CD117+ hematopoietic stem cells isolated from animals subjected to an experimental model of sepsis identified a distinct set of modulated mRNAs encoding distinct histone modifying enzymes - including methyltransferases (Dot1l, Prmt8 and Smyd1) and demethylases (Kdm5b), among others. These results indicate that severe sepsis can modulate the expression of CMEs in hematopoietic stem cells, suggesting distinct changes in the epigenetic signature of these cells. As these CMEs are associated with distinct histone modifications, these results can be used to guide further investigations into the genes targeted by these distinct epigenetic marks.
Multiphoton intravital microscopy analysis of signaling in T cells reveals persistent NFAT activation during dynamic APC scanning. (121.21)
Authors: Marangoni Francesco , Murooka Thomas , Manzo Teresa , Elpek Natalie , Mempel Thorsten 
Published: January 2023

Abstract
The Ca2+ dependent activation and nuclear shuttling of the cytoplasmic transcription factor NFAT is a hallmark of productive T cell receptor (TCR) triggering. However, the kinetics of NFAT activation and the relationship to the Ca2+ dependent migratory stop signal have not been explored in vivo. We used Multiphoton Intravital Microscopy (MP-IVM) to visualize the subcellular dynamics of a fluorescent reporter of NFAT signaling (NFAT-eGFP) in cytotoxic T cells during their antigen-dependent interactions with various APC in lymph nodes (LNs) and in tumor tissue in vivo. During interactions with peptide-loaded B cells representing optimal APC in LNs, t1/2 of NFAT nuclear translocation was 1 minute. Relocation to the cytoplasm upon contact cessation occurred with a slower t1/2 of ~20 minutes. During its delayed nuclear export, NFAT continued to drive transcription of IFN-gamma. We therefore hypothesized that NFAT may facilitate the integration of TCR signals received through serial APC contacts. To test this in vivo, we performed MP-IVM to visualize contacts between cytotoxic T cells and tumor cells, representing suboptimal APCs. We observed that among T cells with continuously nuclear NFAT, ~30% remained motile while engaging in transient, serial contacts with multiple tumor cells. Hence, NFAT slow off-kinetics may constitute a mechanism of short-term biochemical memory enabling the integration of intermittent TCR signaling into a continuous transcriptional response.
A novel function of TRAF6 in TCR signaling (121.26)
Authors: Li Yingqiu , Xie Ji-Ji 
Published: January 2023

Abstract
As an essential ubiquitin E3 ligase in immune responses, the function and mechanism of TNF receptor-associated factor 6 (TRAF6) in adaptive immunity has not been illustrated as well as in innate immunity. Here we show that upon activation of T cells, TRAF6 is recruited to the peripheral ring of the T cells immunological synapse (IS), and is invovled in CD3/CD28-induced NFAT activation. The underlying mechanism is under study.
The SKAP55 dimer stabilizes TCR-induced SLP-76 microclusters (121.27)
Authors: Ophir Michael , Nguyen Ken , Bunnell Stephen 
Published: January 2023

Abstract
The adapter molecule SKAP55 enables the formation of T-cell:APC conjugates, facilitates T-cell cytokine production, and is required for optimal T cell proliferation in response to antigen. However, the molecular basis for the involvement of SKAP55 in these events remains unclear. Here, we demonstrate that both endogenous SKAP55 and exogenous SKAP55 chimeras enter T cell receptor (TCR)-induced signaling microclusters containing the adapter protein SLP-76. Using a SKAP55-deficient Jurkat T cell line, we demonstrate that SKAP55 is required for both the persistence and the movement of SLP-76 microclusters. Furthermore, the recruitment of SKAP55 into microclusters requires the presence of both SLP-76 and ADAP, an intermediary adapter protein capable of interacting with both SLP-76 and SKAP55. In addition, we show that SKAP55 homodimerizes via an N-terminal dimerization motif (DM). Our structure-function analyses indicate that the dimerization domain and the ADAP-interacting Src-homology domain 3 (SH3) domain of SKAP55 are both required for the recruitment of SKAP55 into SLP-76 microclusters, and for the stabilization of SLP-76 microclusters. Importantly, an artificial tandem dimer composed of two functional SH3 domains joined by a flexible linker was sufficient for entry into, and stabilization of these signaling complexes. This data indicates that SKAP55 could contribute to T-cell activation by increasing the overall avidity and stability of TCR-induced SLP-76 microclusters.
Distinct role of RIAM structural elements on IL-2 transcription (121.4)
Authors: Shaw Amy , Patsoukis Nikolaos , Boussiotis Vassiliki 
Published: January 2023

Abstract
RIAM is a novel adaptor that regulates actin polymerization, cell adhesion and PLC-γ1 activation. RIAM contains two coiled-coil regions in the N-terminus, a small proline-rich N-terminus region, a Ras-association (RA) domain, a pleckstrin homology (PH) domain and a large proline-rich C-terminus region. Using RIAM shRNA we determined previously that RIAM is mandatory for IL-2 transcription. The role of the distinct RIAM structural elements in this function remained unclear. In the present study we examined whether RIAM domains have distinct roles in regulating IL-2 transcription and whether this effect is mediated via specific transcription factor binding elements of the IL-2 promoter. Stable Jurkat T cells overexpressing RIAM displayed a dramatic increase in IL-2 transcription as determined by a lusiferase reporter construct driven by the entire IL-2 promoter. Expression of luciferase reporters driven either by AP-1, NFAT or NF-kB promoter elements revealed that NFAT was the dominant target of RIAM. By using various RIAM deletion mutants we found that the effects of RIAM on IL-2 transcription require the RA and PH domains in conjunction with the C-terminus region, while the N-terminus region of RIAM is dispensable for this function. Thus, RIAM promotes IL-2 production by regulating predominantly NFAT-mediated transcription and this effect requires the RA, PH and the C-terminus region of RIAM.
The Splicing Factor ASF/SF2 enhances Interleukin-2 production in human T lymphocytes (121.5)
Authors: Moulton Vaishali , Tsokos George 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease which afflicts mainly women in the reproductive years, and causes painful arthritis, skin disease and complications in the kidneys and brain. Abnormal T lymphocytes in SLE not only regulate autoantibody-producing B cells, but are also responsible for target organ infiltration. Currently, no specific therapeutic strategies target T cell defects. Moreover, there are no known molecular markers to predict disease activity. Aberrant molecular mechanisms responsible for SLE T cell defects are thus promising targets for therapy, as well as potential biomarkers for disease. T cells from patients with SLE express decreased levels of the T cell receptor (TCR) - associated CD3 zeta (ζ) chain, a feature directly linked to their poor interleukin (IL)-2 production. We recently showed that the splicing regulator alternative splicing factor/ splicing factor 2 (ASF/SF2) enhances the expression of CD3ζ chain by limiting the production of an unstable mRNA splice variant. Here, we show that ASF/SF2 expression levels are decreased in T cells from SLE patients, and correlate with CD3ζ chain expression. Moreover, ASF/SF2 expression correlates inversely with SLE disease activity index (SLEDAI). Further, replenishment of ASF/SF2 in SLE T cells restores IL2 production. These results identify ASF/SF2 as a novel regulator of IL2 expression in human T cells and a potential molecular mechanism underlying the altered T cell defect in SLE.
Function of Syntaxin11 in cytotoxic T lymphocytes (121.9)
Authors: Halimani Mahantappa , Pattu Varsha , Junker Christian , Marshall Misty , Matti Ulf , Schwarz Eva , Krause Elmar , Hoth Markus , Rettig Jens 
Published: January 2023

Abstract
Cytotoxic T Lymphocytes (CTLs) form immunological synapses (IS) with antigen presenting cells to kill them. Killing requires the fusion of lytic granules at the IS to release the containing cytotoxic molecules (perforin and granzymes). The fusion process is mediated by SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins. Since mutations within the coding region of syntaxin11 lead to Familial Hemophagocytic Lymphohistiocytosis (FHL4), an immune disorder caused by impaired granule exocytosis. We have investigated the contribution of syntaxin11 to lytic granule release. Using CD3 specific antibodies as a marker for a functional IS, we show that syntaxin11 accumulates at the IS in CTLs. Syntaxin11 was also co-localized with Munc18-2, a docking factor in agreement with the role of Munc18-2 as a syntaxin chaperone in other cell types. Using high resolution nanoscopy (structured illumination microscopy) we determined the subcellular localization of syntaxin11 in CTLs with a syntaxin11 specific antibody. Syntaxin11 was associated with recycling endosomes and mannose 6-phosphate receptor (M6PR) positive compartments. Functional assays using Syntaxin11 specific siRNA (knockdown studies) show a reduction in degranulation and killing efficiency in contrast to control siRNA transfected CTLs. These results support the conclusion that syntaxin11 is required for lytic granule exocytosis.
Naïve anti-Id B cells and Id-specific CD4+ T cells collaborate efficiently to non infectious antigens in the absence of dendritic cells. (122.12)
Authors: Jacobsen Johanne , Schjetne Karoline , Munthe Ludvig , Bogen Bjarne 
Published: January 2023

Abstract
It is thought that activated dendritic cells are needed for induction of T cell responses. However, this makes it difficult to explain immune responses to self-like molecules such as allotypes and idiotypes where no activation of dendritic cells should be involved. We have here generated a double knock-in mouse that expresses prearranged H and L chain V regions of an anti-Id B cell receptor (BCR). By use of anti-Id B cells from this mouse, together with Id-specific CD4+ T cells from T cell receptor (TCR)-transgenic mice, we show that induction of isotype-switched anti-Id Abs depends on the presence of anti-Id B cells, Id-specific T cells, and Id+Ig. Naïve B and T cells were sufficient, and there was no need for MHC-matched dendritic cells. Responses were obtained with physiologically relevant concentrations of B and T cells, and non-adjuvanted Id+ Ig. These results demonstrate that conventional T-B collaboration explains induction of immune responses to non infectious, polymorphic self-like molecules and that dendritic cells are not required.
Repetitive peptide boosting induces functional memory cytotoxic T lymphocytes of a new phenotype (122.4)
Authors: Smyth Kendra , Garcia Karla , Sun Zhifeng , Tuo Wenbin , Xiao Zhengguo 
Published: January 2023

Abstract
Induction of functional memory cytotoxic T lymphocytes (CTLs) holds promise for fighting critical infectious diseases through vaccination, but so far, no effective regime has been identified. One round of immunization is normally not sufficient for generating functional memory CTLs, and subsequent boosting is required. We show here that repetitive intravenous boosting with peptide and adjuvant following priming progressively enhances memory CTLs and drives their differentiation to a unique and long-lasting effector memory phenotype characterized by decreased interferon-γ but increased granzyme B production. The resulting memory CTLs are clearly not immune senescent but are functional and able to provide protection against pathogen challenge. Furthermore, similar enhancement of functional memory CTLs can be achieved regardless of the adjuvant used. Overall, our results suggest that intravenous peptide boosting with adjuvant following priming may be a viable method for generating long-term functional memory CTLs through vaccination.
CD40 Engagement Ablates CTLA-4 expression on Th40 pathogenic cells: A Mechanism for Breach of Tolerance (122.5)
Authors: Wagner David 
Published: January 2023

Abstract
Biomarkers defining pathogenic effector T cells slowly have been forthcoming. Towards this we identified CD4+ cells that express CD40 (CD4CD40), defining these cells as pathogenic in the NOD type 1 diabetes (T1D) model where these cells are unique in their ability to adoptively transfer T1D. To study the origin of CD4CD40 cells and disease pathogenesis we employed a dual transgenic model expressing OVA323-339 peptide as a neo-self antigen on islet beta cells and medullary thymic epithelial cells (mTEC) and a transgenic TCR recognizing the OVA323-339 peptide. CD4CD40 cells and Tregs each recognizing the cognate neo-antigen, rather than being deleted through central tolerance drastically expand in the thymus. DO11.RIPmOVA mice develop autoimmune-type diabetes. In pancreatic lymph nodes CD4CD40 cells are greatly expanded while Tregs remain equivalent to controls and importantly remain functional throughout the disease process, suggesting another breach of tolerance mechanism. DO11.RIPmOVA CD4CD40 cells do not express CTLA-4, a molecule for cell auto-regulation, while DO11 Th40 cells do. CD3/CD28 engagement induces CTLA-4 cell surface expression on DO11 CD4CD40 cells while CD40 co-engagement ablates that induction. Injected antigen (OVA) challenge induces CTLA-4 on CD4CD40 cells while the same antigen expressed endogenously does not. Thus the mechanism of antigen exposure dictates potential tolerance. These data suggest a unique means for CD4CD40 cells to thwart tolerance.
Effects of depletion of CD4+FoxP3+ Treg on development of spontaneous autoimmune thyroiditis (SAT) in WT and B cell deficient (B-/-) NOD.H-2h4 mice (123.10)
Authors: Ellis Jason , Braley-Mullen Helen 
Published: January 2023

Abstract
NOD.H-2h4 mice given NaI in their water develop SAT with chronic inflammation of the thyroid by T and B cells. B-/- mice are resistant to SAT, but develop SAT after transient depletion of Treg by anti-CD25. However, NOD.H-2h4 mice have significant numbers of CD4+FoxP3+ Treg that are CD25-. Generation of mice expressing the human diphtheria toxin receptor (DTR) under control of the FoxP3 promoter allows for selective depletion of Foxp3+ cells by diphtheria toxin (DT). Anti-CD25 depletion of Treg lasts 3-4 weeks, whereas most Treg return 4-5 days after DT treatment. In WT and B-/- FoxP3-DTR NOD.H-2h4 mice, injection of DT eliminates essentially all Treg in blood and spleen within 2 days. As with anti-CD25 depletion, DT treatment allows for SAT development in B-/- mice even though Treg are depleted for only a few days, and SAT in DT-treated WT mice is slightly increased. We established a transfer model in which splenocytes from CD28-/-B-/- mice (effector cells) were cultured with or without sorted Treg from FoxP3-DTR WT or B-/- mice. After transfer to TCRα-/- mice, recipients of Treg from B-/- mice developed significantly less severe SAT than did mice receiving Treg from WT mice. As there is no source of new FoxP3-DTR Treg, DT treatment 2 days after transfer to recipient mice resulted in permanent depletion of Treg. This abrogated the suppression, suggesting that suppression of SAT requires continued inhibition of effectors by Treg during disease development.
Spontaneous development of encephalitogenic T cells is regulated by age-dependent induction of tolerance (123.11)
Authors: Ito Naoko , Boppana Sridhar , Mindur John , Dhib-Jalbut Suhayl , Ito Kouichi 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is an autoimmune disease against CNS and disease onset most often occurs in young adults, suggesting that aging is a critical factor for the development of MS. We examined the effect of aging on the induction of tolerance in the CNS-specific T cells and their differentiation into pathogenic Th1 and Th17 cells in the transgenic (Tg) mice that express HLA-DRB5*0101 and MBP-specific human TCR (3A6) genes isolated from an MS patient. The 3A6-TCR Tg CD4 T cells undergo thymic and peripheral deletion with aging and the surviving CD4 T cells undergo anergy in the periphery. In spite of induction of age-dependent tolerance induction in the MBP-specific CD4 T cells, 3A6 Tg CD4 T cells differentiate into Th1 and Th17 cells in the thymus, migrate into the periphery, and further differentiate into Th1 and Th17 encephalitogenic T cells spontaneously in 5-10-week-old young adult mice. However, increase in age-dependent tolerance reduces the spontaneous development of encephalitogenic T cells. These data suggest that spontaneous development of encephalitogenic T cells is dependent on the balance between age-dependent tolerance induction and spontaneous development of CNS-specific Th1 and Th17 cells.
HLA-DQ trans heterodimer association to type 1 diabetes in East Asian population (123.15)
Authors: Miyadera Hiroko , Ohashi Jun , Tokunaga Katsushi , Japan Diabetes Society Japan Committee on Type Diabetes, 
Published: January 2023

Abstract
HLA-DQ provide the strongest genetic contributions to susceptibility and resistance to type 1 diabetes (T1D). In Europeans, haplotypes carrying non-Asp57β polymorphism in DQB1 (DQA1*03-DQB1*03:02, DQA1*05-DQB1*02) associate strongly to the susceptibility to T1D, while T1D-risk haplotypes in East Asians encode Asp57β (DQA1*03-DQB1*03:03/*04:01). The distinct haplotype associations are ascribed to differences in HLA-DQ-DR haplotype composition and distribution across populations. To understand the mechanistic basis of T1D pathogenesis in East Asian population, we evaluated the disease association of DQA1-DQB1 combinations in trans in T1D case/control samples in Japanese population, which was collected and genotyped by the Committee on Type 1 Diabetes, Japan Diabetes Society. The DQA1 alleles were estimated from DRB1-DQB1 haplotype distributions in general populations, and trans HLA-DQ dimer formation was estimated from the dimerization profile for the entire HLA-DQ alleles (data not shown). Homozygous individuals were also assumed to form trans dimers (dimers identical to cis haplotype) and counted as "trans", in evaluating the associations to T1D. The preliminary result do not suggest the contributions of particular trans DQA1-DQB1 combinations to T1D. The association analyses using the larger sample size will be presented and discussed with the potential mechanistic basis of T1D in Asians.