bluuebunny/crossref_metadata_2025_split huggingface dataset:
15d-PGJ2 ameliorates collagen-induced arthritis by convergence of Th17 to induced-Tregs (83.1)
Authors: Napimoga Marcelo , Carregaro Vanessa , Vieira Silvio , Grespan Renata , Silva João , Cunha Fernando 
Published: January 2023

Abstract
Regulatory T cells (Treg) are CD4+T subtype cells with a critical role in inhibiting autoimmunity. Several works reported efficacy therapeutic of 15d-PGJ2 in autoimmune models as well in vitro is able to generate the differentiation of naïve T lymphocytes to the regulatory profile. However, this prostanoid use and its interrelationship with Tregs during the arthritis rheumatoid are unknown. In view of a therapeutic perspective, we investigate the potential role of 15d-PGJ2 in a model of collagen-induced arthritis (CIA) and its interplay with Tregs-induced anti-inflammatory mechanism. CIA was elicited in DBA male mice by collagen-emulsion injection and then treated with 15-PGJ2 daily during 7 days. 15d-PGJ2 administration at the disease onset attenuated the severity of CIA, reducing clinical score, pain and edema. Furthermore, while the mRNA expression of ROR-γt was reduced, FOXP3 expression was up-regulated in draining lymph nodes cells from 15d-PGJ2-treated mice. In vitro, 15-PGJ2 increased the expression of FOXP3, GITR and CTLA-4, Tregs makers, on CD4+CD25- population, suggesting the induction of Tregs on effector cells. Coculture of Th17 cells with 15d-PGJ2-induced Treg reduced significantly the IL-17 production by collagen and α-CD3 stimuli whereas IL-10 production was enhanced. 15d-PGJ2 converge Th17 lymphocytes to regulatory profile, reducing the number of pathogenic T cells and consequently suppressing the inflammatory immune response. FAPEMIG 097/09
IL-12p35 promotes antibody-induced joint inflammation by activating NKT cells and suppressing TGF-β. (83.14)
Authors: Kim Hye sung , Park Yuna , Ahn Ji Ye , Yun Daesun , Cho Mi La , Hong Seokmann , Kim Ho Youn , Chung Doo Hyun 
Published: January 2023

Abstract
The functional role of IL-12 in rheumatoid arthritis is controversial. Moreover, whether IL-12 contributes to regulation of antibody-induced joint inflammation remains unclear. To address these issues, we explored the functional roles of IL-12 in the K/BxN serum transfer model. IL-12p35-/- and IL-12R2-/- mice were resistant to the development of arthritis. Injection of K/BxN serum into IL-12p40 reporter (yet40) mice induced CD11b+,CD11c+ cells and Gr-1+ granulocytes to produce IL-12p40 in the joints. The levels of IFN-γ, IL-4, and IL-6 production were lower in joint tissues of IL-12p35-/- and IL-12Rβ2-/- mice than B6 mice, whereas that of TGF-β expression was higher. Administering IL-12p35-/- mice recombinant IL-12 or IFN-γ restored joint inflammation and suppressed TGF-β production in joint tissues. Moreover, administering neutralizing αTGF-β mAb enhanced joint inflammation. Among the immune cells that infiltrated joint tissues during antibody-induced arthritis, NKT cells expressed IL-12Rβ2 receptors. Furthermore, the adoptive transfer of splenocytes from B6 or Gr-1+ granulocyte-depleted mice restored joint inflammation in IL-12Rβ2-/- mice as much as in B6 mice, whereas splenocytes from Jα18-/- mice did not. These findings indicate that signals via IL-12 receptors on NKT cells play a critical role in the development of antibody-induced arthritis. In conclusion, the IL-12p35/IFN-γ axis promotes antibody-induced joint inflammation by activating NKT cells and suppressing TGF-β.
Autoreactive cytotoxic T lymphocytes require target tissue stimulus to acquire cytotoxic effector capacity. (83.2)
Authors: Graham Kate , Krishnamurthy Balasubramanian , Santamaria Pere , Thomas Helen , Kay Thomas 
Published: January 2023

Abstract
Cytotoxic T lymphocytes (CTL) are required for the development of autoimmune diseases such as type 1 diabetes. CTL are first activated in lymph nodes (LN) draining target tissue and then concentrate as fully differentiated CTL in the target tissue. We have studied the need for further stimulation of CTL after LN activation and the importance of APCs and the target tissue itself in CTL differentiation. Naïve CFSE-labeled pancreatic β cell specific 8.3-TCR transgenic CD8+ T cells were transferred into NOD mice. Autoreactive CTL proliferated and acquired limited expression of GranzymeB and IFNγ, signatures of cytotoxicity, in the pancreatic LN. CTLs in the islets had proliferated further and acquired higher expression of GzmB and IFNγ. This increased differentiation appeared to take place in the islet because expression of GzmB and IFNγ in CFSE-labeled T cells was similar in peripheral blood and PLN and T cells prevented from migrating from the PLN by FTY720 did not have increased cytotoxic differentiation. Reducing pancreatic β cell antigen presentation affected CTL proliferation but had little effect on differentiation. Increasing the density of antigen on APCs also had more impact on proliferation than differentiation. The data provide in vivo support for a signal required for CTL differentiation, in addition to TCR ligation and co-stimulation, which is produced in the inflamed target tissue. This suggests the target tissue is the critical location for CTL differentiation.
Th17 polarized cells from NOD mice following mycobacterial adjuvant immunotherapy delay type 1 diabetes development (83.26)
Authors: Nikoopour Enayat , Schwartz Jordan , Huszarik Katrina , Sandrock Christian , Kroughly Olga , Lee-Chan Edwin , Singh Bhagirath 
Published: January 2023

Abstract
IL-17 producing T cells are regarded as potential pathogenic T cells in the induction of autoimmune diseases. Previously we have shown that injection of Mycobacteria containing products such as Bacille Calmette-Guerin (BCG) or Complete Freund Adjuvant (CFA), can prevent type 1 diabetes (T1D) in nonobese diabetic (NOD) mice. We injected NOD mice with mycobacterial products subcutaneously and analyzed the IL-17 producing cells from the draining lymph nodes and spleen by restimulating whole cell populations in vitro with or without IL-17 polarizing cytokines. Mice receiving CFA had a concomitant rise in the level of IL-17, IL-22, IL-10 and IFN-g in the draining lymph node and spleen. Adoptive transfer of splenocytes from CFA-injected NOD mice polarized with TGF-b plus IL-6 or IL-23 delayed the development of diabetes in recipient mice. IL-17 producing cells induced by CFA maintained their IL-17 producing ability in the recipient mice. Injection of CFA also changed the cytokine profile of cells in pancreatic tissue by increasing IL-17, IL-10 and IFN-g cytokine gene expression. Compared to wild type mice, injection of CFA into MyD88-/- mice drastically reduced but did not abolish the level of IL-17 in the lymphoid organs and pancreas indicating that the MyD88 pathway is a major pathway through which Mycobacteria exerts its effect. We suggest that the rise in the level of IL-17 after adjuvant therapy in NOD mice has a protective effect on T1D development.
Natural regulatory T cells (Treg) determine post vasectomy sequlae: autoimmune orchitis (EAO) versus testis-specific tolerance. (83.3)
Authors: Wheeler Karen , Luu Brian , Tardif Steve , Rival Claudia , Qiao Hui , Bui Elise , Hardy Daniel , Tung Kenneth 
Published: January 2023

Abstract
Vasectomy (Vx), a popular male contraceptive, causes a persistent epididymal granuloma. Using unilateral Vx (uni-Vx) as an inducer of a localized danger signal, we queried whether Treg control the transition to autoimmunity. When Treg were depleted (CD25 Ab) in uni-Vx mice, frequent and bilateral EAO developed. This was accompanied by T cell activation in the regional lymph node and a robust testis antibody response. CD4+ T cells that produced IFNγ predominated in the diseased testes. CD4+ T cells are sufficient for disease induction as in vivo depletion of CD4+ cells blocked the emergence of EAO and CD4+ cells from uni-Vx mice were able to adoptively transfer disease. We also identified sperm Zonadhesin (Zan) as the major orchitogenic autoantigen. By immunoblot, autoantibodies from uni-Vx mice prominently recognized Zan, and immunization with Zan in adjuvant induced EAO. As EAO induction in Vx men would be devastating, we depleted Treg two weeks following uni-Vx and found they were free of EAO. To test whether uni-Vx in fact induces tolerance to testicular antigens, we compared uni-Vx and Sham-Vx mice in their response to EAO induction by immunization with testis homogenate in CFA. Indeed, uni-Vx mice developed significantly lower EAO scores and autoantibody and T cell proliferative responses. Thus, Treg protect Vx mice from post-Vx EAO by blocking propagation of danger signals to pathogenic autoimmunity while granting systemic tolerance to testis antigens.
Critical mouse strain dependency of IL17A and IFNγ requirements in experimental autoimmune orchitis (EAO) (83.5)
Authors: Rival Claudia , Qiao Hui , Paul Alberta , Tung Kenneth 
Published: January 2023

Abstract
Many autoimmune diseases depend critically on the proinflammatory cytokines IFNγ and IL17, but their relative contribution is controversial. This may be due to variations in mouse strain, adjuvant and autoimmune model. For example, IL17 is deemed critical for EAE and collagen-induced arthritis in B6, whereas IFNγ is critical in proteoglycan-induced arthritis in BALB/c. EAO develops in B6, BALB/c, and (BALB/cxB6) F1 (F1) mice after immunization with testis Ag in CFA and pertussis. Herein, we compared their cytokine requirements using gene KO mice (IFNγ, IL17A) and cytokine Ab blockade. In B6, IL17A is required and IFNγ is redundant. In BALB/c, IL17A and IFNγ are redundant; in fact, EAO still occurs in IL17A and IFNγ double KO BALB/c. In contrast, both IL17A and IFNγ are required in the F1. The variable cytokine dependency may reflect mechanistic differences in EAO amongst these wild type strains, since the testis-infiltrating cells are neutrophil dominant in B6, monocyte dominant in BALB/c, and eosinophil dominant in F1 mice. In addition, the severity of EAO in wild type F1 mice far surpasses either parental strain, indicating genetic complementation. Finally, IFNγ deficient BALB/c developed severe epididymitis and vasitis, which are absent in wild type BALB/c. We have therefore documented fundamental mouse strain differences in IL17A and IFNγ requirement in a single autoimmune disease, and this may reflect strain dependent differences in disease mechanisms.
Regulatory B10 cells have the potential to differentiate into Ab-secreting plasma cells (84.16)
Authors: Smith Susan , Maseda Damian , Bryant Jacquie , Weaver Casey , Tedder Thomas 
Published: January 2023

Abstract
B cells with IL10-dependent regulatory functions have been observed in mouse models of autoimmunity, colitis and in T-dependent immune responses such as delayed-type hypersensitivity. The rare regulatory B10 cell subset that is competent to produce IL10 was examined in the current studies using two distinct lines of reporter mice to track IL10 production. Tiger mice expressed both IL10 and GFP proteins from the same transcript, with GFP expression faithfully marking IL10 production by B10 cells. By contrast, 10BiT mice express Thy1.1 as a separate transcript. While Thy1.1 and IL10 transcripts appeared concurrently as determined by real-time RT-PCR, cell surface Thy1.1 expression was delayed by &gt;24 h and persisted on the cell surface even after a decline in IL10 production. Thus, Thy1.1 expression functioned as a marker for B10 cells after IL10 induction in vivo during later stages of differentiation. Following LPS stimulation in vivo, Thy1.1+ B10 cells upregulated CD138 expression and secreted IgM. Likewise, B10 cells from wild type mice were a major source of secreted Ab following LPS-stimulation ex vivo. Thereby, B10 cells are competent to express IL10 following LPS stimulation in vivo, which is followed by their differentiation into IgM-secreting plasma cells.
Regulation of Immunoglobulin Secretion During Adaptive Immunity (84.17)
Authors: Jones Shannon , Vilen Barbara 
Published: January 2023

Abstract
Regulating BCR-mediated adaptive immune responses and subsequent immunoglobulin (Ig) secretion is critical for normal immune function. Defective regulation could lead to chronic inflammation, autoimmunity, or cancer. Several regulatory mechanisms control the threshold for B cell activation and Ig secretion. One mechanism negatively regulates the threshold for BCR activation through coligation of FcγRIIb and subsequent recruitment of SHIP. It was thought that FcγRIIB was the primary mechanism by which humoral responses were terminated. However, mice deficient in FcγRIIb do not exhibit excessive Ig secretion indicating other regulatory mechanisms must exist. We recently identified two additional mechanisms by which immunoglobulin secretion is attenuated during adaptive immunity. First, upon engagement of FcγRIII on dendritic cells by antibody/antigen immune complexes (ICs), dendritic cells secrete soluble mediators that repress BCR-mediated Ig secretion. Second, an autocrine mechanism functions to inhibit Ig secretion wherein B cells stimulated via the BCR with anti-μ or antigen secrete soluble mediators that repress Ig secretion. These data suggest that in addition to FcγRIIb, soluble factors secreted by both dendritic cells and B cells have a critical role in regulating immunoglobulin secretion during BCR-mediated adaptive immune responses. Studies are underway to define the relative importance of these pathways in terminating Ig secretion during adaptive immunity.
Transcriptional control of rapid recall by memory CD4 T cells (85.10)
Authors: Lai Wendy , Yu Minjun , Okoye Francesca , Keegan Achsah , Farber Donna 
Published: January 2023

Abstract
The defining feature of memory T cells is the capacity for rapid effector function upon restimulation through the T cell antigen receptor (TCR), although the signaling mechanisms controlling memory recall remain undefined. We hypothesized that enhanced transcription factor activation regulated the distinct TCR-coupled functional responses in naive and memory CD4 T cells. We generated memory CD4 T cells by in vitro-priming of naive CD4 T cells from DO11.10 transgenic mice, adoptive transfer into mouse hosts, and recovery 4-8 weeks post-transfer. OVA-specific memory CD4 T cells produced high levels of IFN-γ early (6hrs) after antigen stimulation, compared to IFN-γ production after 24-48hrs stimulation of OVA-specific naive CD4 T cells. Early IFN-γ production by antigen-stimulated memory CD4 T cells occurred in the absence of upregulation of the T-bet transcription factor, while IFN-γ production following naive CD4 T cell activation was associated with high T-bet expression. Chromatin immunoprecipitation (ChIP) analysis revealed that NFκB, but not T-bet was bound to the IFN-γ promoter in memory CD4 T cells early after TCR stimulation. In addition, expression of the active nuclear p50 subunit of NFκB was increased in resting and activated memory versus naive CD4 T cells, and inhibition of NFκB activity impaired early memory T cell recall. These results reveal a molecular mechanism for immediate recall responses in memory CD4 T cells through enhanced NFκB activity.
Comprehensive and semi-quantitative TCR repertoire analysis with a novel multiplex PCR method and 454 sequencing (85.3)
Authors: Han Jian , Wang Chunlin , Sanders Catherine , Yang Qunying , Schroeder Harry , Wang Elijah , Babrzadeh Farbod , Gharizadeh Baback , Myers Richard , Hudson James , Davis Ronald 
Published: January 2023

Abstract
CDR3 sequences, composed by V(D)J combination, form the center of the antigen binding site where they often play a critical role in defining the affinity and specificity of the receptor for individual peptide-MHC complexes of both the TCRα and TCRβ chains. The goal of our study was to produce comprehensive, unrestricted profiles of TCR diversity among key developmental and effector subsets of T cells isolated from the blood of a single, healthy donor at sequence-level resolution using a novel multiplex PCR method combined with Roche 454 Life Sciences high-throughput sequencing technology. From the sequence reads, about 1.48 million CDR3 intervals were identified, totaling 169,977 and 113,290 unique CDR3 intervals for TCRα and for TCRβ, respecitively. Our data also show numerous examples of identical CDR3 sequences shared by different T subsets. Using the compound Poisson process model, we estimated that the diversity of the TCRα and β chains expressed by our donor is around 0.47 x 106 and 0.35 x 106 unique CDR3 nucleotide sequences, respectively. Our comprehensive data demonstrates that our new method has overcome past challenges in studying the T cell immune repertoire and is highly sensitive, repeatable, and semi-quantitative. This approach provides a useful tool for assessing immune competence, tracking T cell expansion kinetics, assessing vaccine efficiency, and detecting antigen-specific T cell clones in patients with infection or cancer.
Regulation of IL-13 in mast cells by the Let-7 miRNA family (86.15)
Authors: Takemoto Clifford , Gamper Christopher , Lee Youl-Nam , Mendell Joshua , Brandal Stephanie , Powell Jonathan , McDevitt Michael 
Published: January 2023

Abstract
In mast cells, IL-13 protein is robustly expressed with IgE activation; IL-13 mRNA transcript also increases, but rapidly returns to baseline levels within several hours. Based on these observations, we postulated that miRNAs may regulate IL-13 protein expression at the post-transcriptional level. miRNAs play roles in a number of biologic processes but little is known about their function in mediating allergic disease. To explore if miRNAs contribute to IL-13 regulation and other IgE responses, we performed a microarray screen for miRNAs regulated by IgE in both mouse and human mast cells. We found that IgE stimulation resulted in widespread depression of miRNAs, including downregulation of the Let-7 miRNA family. We looked for proteins expressed in IgE activated mast cells that were potentially targeted by Let-7. We found a highly conserved Let-7 binding site in the 3’UTR of the IL-13 gene. We further demonstrate that the IL-13 UTR is regulated by Let-7; forced expression of Let-7 represses expression of a reporter gene with the IL-13 UTR, and repression is abrogated by mutation of the Let-7 binding site. Conversely, we show that Let-7 inhibition results in increased expression of a reporter gene with the IL-13 UTR, either by transfection of “antagomirs”, or by overexpression of the Let-7 family inhibitor, LIN28B. These results suggest that in mast cells, IL-13 protein expression is regulated by Let-7 miRNAs and support a role for miRNAs mediating IgE responses.
Contrasting requirements for DAP12 in receptor-mediated mast cell activation (86.4)
Authors: Smrz Daniel , Iwaki Shoko , Metcalfe Dean , Gilfillan Alasdair 
Published: January 2023

Abstract
By inducing FcϵRI aggregation, antigen/IgE promotes mast cell cytokine production; a response markedly enhanced by specific TLR agonists. Critical to the ability of FcϵRI to activate mast cells is the recruitment of the tyrosine kinase Syk via the FcϵRIγ chains. Recent reports in other cell types have indicated that TLR’s may alternatively signal via the adaptor molecule DAP12 which also has the ability to bind Syk following tyrosine phosphorylation. We therefore examined whether DAP12 similarly regulates TLR-mediated responses in mast cells. DAP12 was confirmed to be expressed in both human and mouse mast cells (BMMCs) and, following its phosphorylation by pervanadate treatment, DAP12 recruited Syk. Although the TLR agonists LPS, Pam3Cys, and MALP2 induced cytokine production and synergistically enhanced this response mediated by FcϵRI, they failed to increase basal DAP12 phosphorylation. Furthermore, no up-regulation or down-regulation of TLR-mediated responses, nor FcϵRI-mediated responses, was observed in DAP12-/- BMMCs. In contrast, DAP12 phosphorylation and Syk recruitment were observed in mast cells following concanavalin A (Con A)-induced aggregation of mannose-glycosylated receptors, and these responses, together with ConA-induced degranulation, were substantially reduced in the DAP12-/- BMMCs. These data show that in mast cells DAP12 does not regulate TLR- or FcϵRI-mediated responses, but is required for responses elicited by mannose-glycosylated receptors.
Stat5 is Activated by FceRI via Fyn Kinase (86.7)
Authors: Ryan John , Barnstein Brian 
Published: January 2023

Abstract
We have recently found that the transcription factor Stat5 is rapidly activated by IgE crosslinkage, and that its expression is critical to IgE-mediated degranulation, LTB4 production, cytokine secretion, and survival signals. Stat5KO mast cells induced cytokine mRNAs normally following IgE crosslinkage, but these mRNAs were not sustained over time, and were degraded at twice the rate observed in wild type cells. We find that Stat5 is associated with the IgE receptor after antigen-mediated activation. Moreover, cholesterol depletion or Fyn kinase deletion prevents Stat5 tyrosine phosphorylation in response to IgE crosslinkage. In contrast, the Lyn, Syk, MAPK, and PI-3 kinase pathways do not appear to regulate Stat5 tyrosine phosphorylation via the IgE receptor. We also find that Stat5 is serine phosphorylated during IgE signaling. These data suggest that Stat5 is activated through a lipid raft- and Fyn-dependent pathway. Our work demonstrates that Stat5 is a critical factor in IgE-induced mast cell activation that could provide a new clinical target for mast cell-associated inflammatory diseases.
Aryl Hydrocarbon Receptor independent production of IL-17A in a murine model of Hypersensitivity Pneumonitis (87.12)
Authors: Mohinta Sonia , Perdew Gary , August Avery 
Published: January 2023

Abstract
AhR (Aryl hydrocarbon Receptor) is a cytosolic transcription factor functioning as a sensor for environmental toxins. Recently, AhR has been suggested to have a cardinal role in Th17 biology. Although AhR is not a direct regulatory factor for Th17 differentiation its activation is required for the functional differentiation of Th17 cells, and production IL-22. To study the role of AhR in T cell differentiation we have used selective ligands of AhR in an in vitro assay and found that AhR agonist beta-naphthoflavone enhances IL-17 production whereas an AhR inhibitor suppresses it, both at the level of transcription and translation. The Th2 cytokine IL-4 was suppressed by beta-naphthoflavone and induced by the inhibitor and the Th1 cytokine IFNγ was inhibited by both the compounds. To further investigate the role of AhR in Th17 biology we used a well established Th17 dominated murine model of hypersensitivity pneumonitis mediated by a thermophilic actinomycete Staphylopolyspora rectivirgula (SR). Analysis of the cytokine transcripts from the SR exposed lungs revealed that IL-17 was not only expressed in WT mice but was more highly expressed in Ahr-null mice. These data suggest that the AhR may regulate cytokine production by other T cell subsets, and that the requirement for the AhR in IL-17 expression may be restricted to T cells. Further work is required to determine the role of the AhR in the innate immune cells, which are potential sources of IL-17.