bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pinning down Bruton’s tyrosine kinase (Btk) (B26)
Authors: Vargas Leonardo , Yu Liang , Mohamed Abdalla J. , Berglöf Anna , Smith C. I. Edvard 
Published: January 2023

Abstract
Bruton’s tyrosine kinase (Btk) is a nonreceptor tyrosine kinase belonging to the Tec family of Src-related protein tyrosine kinases (PTKs). Btk is predominantly expressed in B-lymphocytes as well as in myeloid and erythroid progenitor cells. It has been shown that Btk plays critical roles in B-lymphocytes development, differentiation, and signaling. Mutations in Btk cause X-linked agammaglobulinema in humans and X-linked immunodeficiency in mice. However, the mechanism of activation and signaling of this enzyme has not been fully investigated.
The peptidyl-prolyl cis/trans isomerase (PPIase) Pin1 is an important regulator of cell proliferation and DNA-replication. Recent report shows that pin1 is overexpressed in diffuse large B cell lymphoma.
In both cell lines and Pin1 knock-out mice experiment, We identified that the Pin1 is a negative regulator of Btk, controlling its expression level by reducing its half-life, and the negative regulatory effect of Pin1 is dependent on a functionally intact Btk. We also found that pin1 interact with Btk in a cell cycle dependent manner, Phosphorylation of Serine 21 leads to Pin1 binding and regulation only during mitosis, whereas phosphorylation of Serinev115 leads to Pin1 binding and regulation specifically in the resting cells. Our results indicate that, a key regulator of Btk activity and half-life, Pin1 prolyl isomerase controls a critical non–receptor tyrosine kinase for normal B cell biology.
This study was supported by the Swedish Cancer Fond, The Magnus Bergvall Foundation, the Wallenberg Foundation and the European Union Grant EURO-POLICY-PID.
Phosphorylation and ubiquitination of the I kappa B kinase complex by two distinct signaling pathways (B29)
Authors: shambharkar prashant 
Published: January 2023

Abstract
The IκB kinase (IKK) complex serves as the master regulator for the activation of NF-κB by various stimuli. It contains two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKKα/β at its activation loop, and the K63-linked ubiquitination of NEMO. However, the molecular mechanism by which these inducible modifications occur remains undefined. Here, we demonstrate that CARMA1, a key scaffold molecule, is essential to regulate NEMO ubiquitination upon T cell receptor (TCR) stimulation. However, the phosphorylation of IKKα/β activation loop is independent of CARMA1, or NEMO ubiquitination. Further, we provide evidence that TAK1 is activated and recruited to the synapses in a CARMA1-independent manner and mediate IKKα/β phosphorylation. Thus, our study provides the biochemical and genetic evidence that phosphorylation of IKKα/β and ubiquitination of NEMO are regulated by two distinct pathways upon TCR stimulation.
The protective effect of the NOD.Idd3 genetic interval is associated with enhanced regulatory T cell function and IL-10 production (B37)
Authors: Anderson Ana C , Chandwaskar Rucha , Kuchroo Vijay K 
Published: January 2023

Abstract
The Idd3 genetic interval confers protection against multiple autoimmune diseases, including type 1 diabetes and experimental autoimmune encephalomyelitis (EAE). However, the cellular and molecular mechanisms by which the Idd3 locus mediates suppression of autoimmunity have not been analyzed. The favored candidate gene in this interval is Il2, which has been shown to be polymorphic between susceptible and resistant strains of mice. IL-2 regulates the growth/death of effector T cells as well as the generation/maintenance of regulatory T cells (Tregs). We have examined both Tregs and effector T cells in NOD and NOD.Idd3 congenic mice and find that NOD.Idd3 Tregs are more suppressive and NOD.Idd3 effector T cells produce more IL-10 when compared to NOD-derived T cells. Interestingly, we find that both these effects are driven by NOD.Idd3-derived antigen presenting cells, suggesting that the protective effect of Idd3 is due to alterations in the APC compartment and not T cells themselves.
Sterile protection against malaria infection requires TAP in spite of completely operative TAP-independent vacuolar cross-presentation pathway (B40)
Authors: Liepinsh Dmitry J , Steers Nick , Schwenk Robert J , Krzych Urszula 
Published: January 2023

Abstract
Induction of long-lasting protective immunity to malaria by repetitive immunization with P. berghei γ radiation-attenuated sporozoites (γ-spz) requires MHC class I-restricted CD8+ T cells, implying that γ-spz/liver stage derived antigens have to be presented through one of the cross-presentation pathways. Based on accumulation of proliferating and IFN-γ producing effector/memory CD8+ T cells in the livers of TAP−/− mice, we showed that TAP-independent vacuolar pathway efficiently operates in vivo during priming and subsequent boosts with γ-spz. Likewise, infectious sporozoite challenge increased the number of IFN-γ+ CD8+ T cells in γ-spz immune TAP−/− mice and induced IFN-γ production by wt γ-spz immune CD8+ T cells transferred into TAP−/− environment suggesting that γ-spz/liver stage derived MHC class I specific peptides generated in a TAP-independent manner participate in response to infectious sporozoites. Nevertheless, the pattern of IFN-γ secretion, parasitemia and survival data upon infectious sporozoite challenge clearly indicated that TAP-associated antigen processing is indispensable for sterile protection.
An automatically curated MHC ontology for intelligent immunogenetic information retrieval (B42)
Authors: DeLuca David S. , Beisswanger Elena , Hahn Udo , Blasczyk Rainer 
Published: January 2023

Abstract
Accurate information retrieval of scientific articles is complicated by the intricacies of natural language. Ontologies are useful for formalizing scientific concepts and providing a foundation to mediate between formal, computationally accessible, representations and informal natural language expressions. The terminology associated with the MHC exemplifies the need for a sophisticated translation process between a natural language query and the relevant documents. For example, a researcher searching for “peptides that bind MHC” should be presented with a text containing “peptides were eluted from HLA-A2.” To achieve this goal, we have developed a multi-species MHC ontology which encompasses all human MHC alleles and serologic groups. Because of the rapid rate of new allele discovery, allele incorporation is automated using the IMGT/HLA and IPD-MHC databases. In the context of the StemNet knowledge management project, this MHC ontology contributes to machine-learning-driven text annotation, as well as to search-string interpretation and mapping. In this way, StemNet aims to offer researchers a platform to efficiently access the goldmine of clinically relevant immunogenetic information, which is otherwise inaccessible by standard search engines and databases.
This work was financed by the Federal Ministry of Education and Research, Germany, funding number 01DS001C; the authors are solely responsible for content.
Phenotypic changes induced by IL-12 priming regulate effector and memory CD8 T cell differentiation (B48)
Authors: Lee Jee-Boong , Lee Kyoo-A , Chang Jun 
Published: January 2023

Abstract
Inflammatory cytokines such as IL-12 provide important signals for optimal activation of naïve T cells in addition to TCR and costimulatory signals. In the previous study, we demonstrated that IL-12 provides survival signals to the CD8 T cells and thus increases the generation of effector and memory CD8 T cells. In the present study, to investigate the mechanisms by which IL-12 priming contributes to differentiation and survival of CD8 T cells, we searched the differentially regulated genes and markers by IL-12 during antigenic stimulation. Here, we show that IL-12 priming results in the increased subpopulation of CD127hi cells, which is known to develop into long-lived memory cells. We also found that IL-12 priming dramatically induces IL-10 expression from activated CD8 T cells. Direct IL-10 priming of CD8 T cells resulted in the significant increase of effector and memory CD8 T cell population after adoptive transfer and this priming effect is closely associated with less susceptibility to apoptosis. Although IL-10 is known as a cytokine with important anti-inflammatory and immunosuppressive properties, these results have shown that IL-10 has a direct and positive effect on the survival of CD8 T cells. Together, our results suggest that cytokine environment such as IL-12 and IL-10 play important roles, at the early stage of antigenic stimulation, in regulating differentiation of activated CD8 T cells into effector and memory cells.
*This work was supported by the grant R11-2002-098-05005-0 from Korea Science and Engineering Foundation and by the grant R15-2006-020 from the NCRC program of the Ministry of Science & Technology and the Korea Science and Engineering Foundation
Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor (B52)
Authors: Chang Seon Hee , Park Heon , Dong Chen 
Published: January 2023

Abstract
Interleukin (IL)-17, the founding member of the IL-17 cytokine family, is the hallmark of a novel subset of CD4+ T cells that is regulated by TGFbeta, IL-6, and IL-23. IL-17 plays an important role in promoting tissue inflammation in host defense against infection and in autoimmune diseases. Although IL-17 has been reported to regulate the expression of proinflammatory cytokines, chemokines, and matrix metalloproteinases, the signaling mechanism of IL-17 receptor has not been understood. An earlier study found that IL-17 activates NF-kappaB and MAPK pathways and requires TRAF6 to induce IL-6. However, it is unknown what molecule(s) directly associates with IL-17 receptor to initiate the signaling. We demonstrate here that IL-17 receptor family shares sequence homology in their intracellular region with Toll-IL-1 receptor (TIR) domains and with Act1, a novel adaptor previously reported as an NF-kappaB activator. MyD88 and IRAK4, downstream signaling components of TIR, are not required for IL-17 signaling. On the other hand, Act1 and IL-17 receptor directly associate likely via homotypic interaction. Deficiency of Act1 in fibroblast abrogates IL-17-induced cytokine and chemokine expression, as well as the induction of C/EBPbeta, C/EBPdelta, and IkappaBzeta. Also, absence of Act1 results in a selective defect in IL-17-induced activation of NF-kappaB pathway. These results thus indicate Act1 as a membrane-proximal adaptor of IL-17 receptor with an essential role in induction of inflammatory genes. Our study not only for the first time reveals an immediate signaling mechanism downstream of an IL-17 family receptor but also has implications in therapeutic treatment of various immune diseases
Interleukin-22 Induces Lipopolysaccharide Binding Protein in Hepatocytes: a Potential Systemic Role of Interleukin-22 in Crohn’s Disease (B60)
Authors: Wolk Kerstin , Witte Ellen , Hoffmann Ute , Döcke Wolf-Dietrich , Endesfelder Stefanie , Asadullah Khusru , Sterry Wolfram , Volk Hans-Dieter , Wittig Bianca Maria , Sabat Robert 
Published: January 2023

Abstract
Crohn’s disease (CD) is characterized by intestinal infiltration of activated immune cells and distortion of the gut architecture. Here, we demonstrate that IL-22, a cytokine that is mainly produced by activated Th1 and Th17 cells, was present in high quantities in the blood of CD patients in contrast to IFN-[gamma] and IL-17. In a mouse colitis model, IL-22 mRNA expression was elevated predominantly in the inflamed intestine but also in the mesenteric lymph nodes. Simultaneously, IL-22BP showed strong a constitutive expression in the gut and lymph nodes and was decreased in the inflamed intestine. To investigate the possible role of systemic IL-22 in CD, we administered IL-22 to healthy mice and found an up-regulation of LPS binding protein blood levels reaching concentrations known to neutralize LPS. This systemic up-regulation was associated with increased hepatic but not renal or pulmonary LBP mRNA levels. IL-22 also enhanced the secretion of LBP in hepatocytes in vitro. This increase was mainly transcriptionally regulated and synergistic with that of other LBP inducers. Finally, elevated LBP levels were detected in CD patients and the mouse colitis model. These data suggest that systemic IL-22 may contribute to the prevention of systemic inflammation provoked by LPS present in the blood of CD patients through its induction of hepatic LBP.
Thromboembolic stroke promotes the formation of the inflammasome complex (B70)
Authors: Abulafia Denise P , de Rivero Vaccari J Pablo , Lozano J Diego , Ragan Timothy J , Keane Robert W , Dietrich W Dalton 
Published: January 2023

Abstract
Inflammatory responses contribute to the pathogenesis of cerebral ischemia and stroke. Activated caspase-1 cleaves the pro-inflammatory cytokines IL-1β and IL-18, initiating a cascade of detrimental inflammatory events. Cell culture studies of macrophages have reported that activation of caspase-1 involves the formation of a macromolecular complex termed the inflammasome. Whether this complex is present after cerebral ischemia is unknown. Here, we utilized a clinically relevant model of thromboembolic stroke in mice to investigate the formation of the inflammasome and subsequent activation of inflammatory responses. Our results demonstrate for the first time that cerebral ischemia triggered the formation of a high molecular weight complex comprised of caspase-1, caspase-11, the adaptor protein ASC (apoptosis-associated speck-like protein with CARD) and NALP1 (NACHT/LRR/pyrin domain-containing protein 1) in the cerebral cortex, 24 hr after ischemia. Formation of the inflammasome complex resulted in activation of caspase-1 and cleavage of IL-1β and IL-18. Immunohistochemical analysis revealed the presence of inflammasome proteins in cortical neurons and inflammatory cells. Finally, the therapeutic potential of targeting the inflammasome after ischemia was demonstrated by reduced cytokine activation in mice treated with a neutralizing antibody against NALP1.
IgA plasma cell migration to the lactating mammary gland is mediated by an alpha4 dependent, MAdCAM-1 independent pathway (B71)
Authors: Martino Ben , Wilson Eric 
Published: January 2023

Abstract
It has been previously shown that the accumulation of immunoglobulin A (IgA) antibody secreting cells (ASC) in the lactating mammary gland leads to secretion of antibodies into mothers’ milk and their passive transfer to the suckling newborn. The lactating mammary gland also provides a unique model in understanding the molecular mechanisms governing lymphocyte homing to the common mucosal immune system. Lymphocyte homing is mediated through a multi-step process involving the vascular expression of adhesion molecules and chemokines, as well as lymphocyte expression of cognate adhesion molecule ligands and chemokine receptors. We have previously shown that the accumulation of IgA ASC to the lactating mammary gland is highly dependant on the chemokine CCL28. However, the adhesion molecules governing this homing event have not been defined. Here we show that IgA ASC homing to the lactating mammary gland is blocked by the addition of function blocking anti-alpha4 antibodies but not function blocking anti-MAdCAM-1 antibodies. These results suggest that IgA ASC homing to the lactating mammary gland is mediated in an alpha4 beta7/MAdCAM-1 independent manner.
Hypersensitiveness to Diphtheria Bacterial Products
Authors: Neill James M. , Fleming William L. , Sugg John Y. , Gaspari E. L. 
Published: January 2023

Summary
Previous evidence indicative that toxin is the substance involved in C's hypersensitiveness was based upon the consistent association of high toxin content of test material with high degree of hypersensitive reactivity and of low or no toxin content with weak or no hypersensitive reactivity. The evidence in this paper was based upon the constant association between the antitoxin content of serum and the capacity of the serum to neutralize the hypersensitive agent when the toxin-containing filtrate is incubated with the serum before injection in individual C. Experiments with similar results were obtained with antitoxin-containing serum of horses, rabbits, and men. With the rabbit sera the use of an “antibacterial” as well as an “antitoxic” serum made it possible to show not only that a serum containing antitoxin was able to neutralize the hypersensitive agent but also that a serum rich in other antidiphtheria antibodies was unable to neutralize it. The most convincing results were obtained with human sera because it was possible by choice from a large number to select for the tests more purely “antitoxic” sera than could be obtained by the laboratory immunization of animals. The selected human sera, although containing no precipitins and no or only traces of “group agglutin,” were able to neutralize the agent of the hypersensitive reaction. Further experiments demonstrated a quantitative relationship between the antitoxin content and the amount of the respective serum required to neutralize the substance hypersensitively reactive with individual C.
Stomatin-like protein 2: a link between T cell activation and mitochondrial function (35.19)
Authors: Christie Darah , Lemke Caitlin , Hatch Grant , Madrenas Joaquín 
Published: January 2023

Abstract
During a study to characterize the proteome of lipid raft microdomains of activated human T cells we identified stomatin-like protein 2 (SLP-2). We have previously shown that T cell activation through the TCR leads to up-regulation of SLP-2 expression, which in turn correlates with enhanced T cell effector responses. Since in human T cells the major pool of SLP-2 is associated with mitochondria, we examined the function of this protein in mitochondria during T cell activation. Here, we report that up-regulation of SLP-2 expression increases mitochondrial mass and count. Such an effect correlates with an increase in the expression of the nuclear transcriptional co-activator PGC-1α, in lipid biosynthesis linked to mitochondrial membrane biogenesis, and in mitochondrial DNA replication. As expected, these changes translate into an increase in both cellular and mitochondrial ATP levels, higher mitochondrial uptake of calcium, and enhanced resistance to apoptosis through the intrinsic pathway. Based on these results we propose that SLP-2 expression is a key regulatory step for mitochondrial biogenesis and function in response to T cell activation.
In vitro PTEN deletion in peripheral T cells enhances activation but does not replace CD28 costimulation or prevent anergy (35.37)
Authors: Locke Frederick L , Zha Yuan-yuan , Gajewski Thomas F 
Published: January 2023

Abstract
PTEN plays a pivotal role in T cell development by negatively regulating the PI3K signaling pathway important for activation, growth, and proliferation. In Cre/loxp mouse models when PTEN is deleted during thymogenesis, peripheral T cells show CD28-independent IL-2 production and are relatively resistant to anergy induction. These animals also develop autoimmunity and T cell lymphomas. However, the consequences of PTEN deletion directly in peripheral T cells are not known, and we hypothesized that much of this phenotype might be explained by the elimination of PTEN during thymic development. The use of CAR Tg-PTENflox/flox mice allowed deletion of PTEN using a Cre adenovirus in vitro. PTEN-deleted splenic T cells or Th1 clones exhibited enhanced IL-2 and IFN-gamma production and proliferation upon TCR/CD28 engagement. Gene expression profiling revealed a subset of induced genes that were augmented upon PTEN deletion. However, PTEN-deficient T cells still required CD28 costimulation for IL-2 production and were not resistant to anti-CD3-induced anergy. Our results indicate that deletion of PTEN can augment the activation of post-thymic T cells but does not mediate CD28-independence or anergy resistance. Ongoing experiments will determine if the absence of PTEN protein in post thymic T cells will lead to improved immune responses in vivo, and if overt autoimmunity or lymphomagenesis will occur.
Trogocytosis leads to sustained signaling and selective survival of CD4+ T cells (35.44)
Authors: Osborne Douglas G. , Wetzel Scott A 
Published: January 2023

Abstract
Antigen recognition by CD4+ T cells leads to large-scale spatial and temporal molecular redistributions, forming the immunological synapse. We have previously shown that upon dissociation, T cells capture large membrane fragments from the antigen presenting cell directly from the immunological synapse. The mechanism and biological significance of this process, termed trogocytosis, is still unclear. In this study we examine the impact that trogocytosis has on the individual T cell after capturing molecules from the antigen presenting cell. We employed murine fibroblast and dendritic cell lines expressing an I-Ek molecule loaded with a covalently attached antigenic peptide (moth cytochrome C 88-103) and containing a GFP-tagged cytoplasmic tail as antigen presenting cells for T cells from a peptide-specific TCR transgenic mouse. Using a combination of high-resolution microscopy, ELISA and flow cytometry, we have shown that the transferred material is retained on the surface of the T cell and is associated with sustained signaling after removal of the antigen presenting cells. The extent of transfer correlates with increased proliferation and sustained survival of the transfer-positive cells in vitro. These findings suggest that trogocytosis may lead to sustained signaling and survival, potentially altering the effector functions of T cells.
Funded By NIH COBRE 2P20RR017670 (Subproject 5)
Identifying ZAP-70 kinase-dependent and -independent functions in T cells using a chemical genetic approach (35.5)
Authors: Au-Yeung Byron B , Levin Susan E , Zhang Chao , Shokat Kevan , Weiss Arthur 
Published: January 2023

Abstract
The tyrosine kinase ZAP-70 activates signals proximal to the TCR and is critical for the activation of downstream signal pathways. To identify which T cell functions require ZAP-70 kinase activity, our lab has generated a novel mouse that expresses an analog-sensitive ZAP-70 mutant that can be inhibited specifically by an analog of the Src family kinase inhibitor PP1. This titratable, chemical genetic approach gives us the ability to rapidly and specifically inhibit ZAP-70 activity in primary mouse T cells. We asked whether naïve and effector responses upon TCR stimulation required ZAP-70 activity. TCR induced calcium mobilization, upregulation of CD69, and proliferation were highly dependent on ZAP-70 activity. Similarly, effector cytokine production by primed CD4+ and CD8+ cells was ZAP-70 kinase-dependent. Inhibition of ZAP-70 activity also severely impaired CD8+ cytolytic activity. In contrast to conventional CD4+ and CD8+ T cells, we observed that CD4+ CD25+ Treg suppress CD4+ CD25- T cell proliferation, even in the presence of the ZAP-70 inhibitor. Thus, while conventional T cell activation and function are ZAP-70 kinase dependent, CD4+ CD25+ Treg suppressive function appears to be ZAP-70 kinase-independent. Our results imply that an inhibitor of the WT form of ZAP-70 could be effective for the attenuation of T cell-mediated pathology.