bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbiota antigen specific Th17 cells induce colitis and promote Th1 cell response through IL-17 induction of innate cell IL-12 and IL-23 production (47.3)
Authors: Feng Ting , Qin Hongwei , Wang Lanfang , Benveniste Etty , Elson Charles , Cong Yingzi 
Published: January 2023

Abstract
Both Th1 and Th17 cells have been implicated in the pathogenesis of IBD and experimental colitis. However, the complex relationship between Th1 and Th17 cells has not been completely analyzed. Although it has been shown recently that Th17 cells can convert into Th1 cells, the underlying in vivo mechanisms and the role of Th1 cells converted from Th17 cells in colitis pathogenesis are still largely unknown. By using Thy1.1-IFNγ reporter mice and IL-17 capture technique, we generated Th1 and Th17 cells of high purity from immunodominant microbiota antigen CBir1 flagellin specific TCR transgenic mice. Highly purified Th1 and Th17 cells differentially induced colitis, in that Th1 cells induced mild, whereas Th17 cells induced severe colitis when transferred into TCRβxδ-/- mice. In the colitic Th17 recipients, substantial IFNγ+ Th1 cells emerged in intestinal lamina propria. Colonic tissues of Th17 recipients produced high levels of IL-12 and IL-23. IL-17 treatment induced BMDC IL-12 and IL-23 production in vitro. Administration of anti-IL-17 mAb to Th17 recipients abrogated colitis development, blocked colonic IL-12 and IL-23 production, and inhibited T cell IFNγ production. Furthermore, colon-conditioned medium of colitic Th17 cell recipients promoted IFNγ production by Th17 cells, which was inhibited by the addition of anti-IL-12 and anti-IL-23 mAb. These data indicate that Th17 cells promote Th1 cells through IL-17 induction of mucosal innate cell IL-12 and IL-23 production.
Role of MKP-1 in an IL-10 knockout murine inflammatory bowel disease model (47.7)
Authors: Wancket Lyn , Matta Ranyia , Barnard John , Grieves Jessica , Nelin Leif , Cato Andrew , Liu Yusen 
Published: January 2023

Abstract
IBD is a chronic intestinal inflammatory disease that often has extra-intestinal manifestations. We examined the role of the MAPK phosphatase Mkp-1 in a mouse model of IBD. Mkp-1+/+/Il-10+/+, Mkp-1-/-/Il-10+/+, Mkp-1+/+/Il-10-/-, and Mkp-1-/-/Il-10-/- (dKO) mice on a 129 background were housed in a specific pathogen-free environment. Colitis signs were evaluated using a clinical scoring system, histological examination, and cytokine analysis. Most dKO mice developed severe rectal prolapse, peri-ocular lesions, and high clinical scores, signs generally not seen in Il-10 KO mice. dKO colons had extensive chronic and neutrophilic colitis, mucosal hyperplasia, and higher histological IBD scores than Il-10 KO colons. dKO eyelids and conjunctival mucosa were thickened and had neutrophilic and lymphoplasmocytic conjunctivitis. After LPS treatment, splenocytes and lymph node cells isolated from dKO mice had more robust production of Th-1 cytokines than cells from Il-10 KO mice. dKO colons contained higher levels of Th-1 cytokines and IL-17, and exhibited greater p38 and ERK activation, than did Il-10 KO colons. These data indicate that loss of Mkp-1 skews host immunity towards an exaggerated Th-1/Th-17 response and provide novel insights on the interaction between Mkp-1 and IL-10 in colitis models. Our studies support a pivotal role of Mkp-1 as a brake in the mucosal immune response to limit IBD development.
Conversion of conventional T cells to Tregs within the eye and the dual role of the vision related molecule, retinoic acid, in ocular immune privilege (48.1)
Authors: Zhou Ru , Horai Reiko , Mattapallil Mary , Rigden Rachael , Villasmil Rafael , Caspi Rachel 
Published: January 2023

Abstract
Ocular immune privilege protects the eye from immune damage in part through TGFβ. Retinoic acid (RA) is abundant in the eye, as it participates in the chemistry of vision. However, its role, if any, in immune responses involving the eye is unknown. RA-synthesizing enzymes RALDH1, 2 and 3 were expressed in the cornea and retina. Aqueous humor (AH) massively induced Foxp3 expression in purified CD4+ T cells stimulated through the T cell receptor, while suppressing their proliferation and acquisition of effector function, as judged by reduction of lineage-specific transcription factors and effector cytokines for Th1, Th2 and Th17. AH-induced Foxp3+ T cells expressed CD25, GITR, CTLA4, CD103 and were functionally suppressive. The effect of AH was reversed by antagonizing either RA or TGFβ signaling and involved TGFβ-driven upregulation of RARα. Foxp3 expression was reduced upon removal of AH from culture, but was stabilized by the DNA demethylating agent 5-AZA. Importantly, naive retina-specific (but not polyclonal) T cells, injected into the eyes of live mice, were converted in vivo into Foxp3+ cells. In contrast, previously primed T cells exposed to AH on 2nd stimulation were resistant to suppressive effect of AH. Thus, RA in the eye plays a dual role: in vision and in immune privilege, by local induction of Tregs. However, primed effector cells are relatively insensitive to AH, helping to explain occurrence of uveitis in the face of an inhibitory ocular microenvironment.
Nuclear and cytoplasmic antibodies in severe periodontytis (48.16)
Authors: Aguilera galaviz Luis , Padilla Bernal María , Aceves Medina María , Sanchez Rodríguez Sergio , Lopez Luna María 
Published: January 2023

Abstract
Periodontitis is bacterial infection of tooth-supporting tissues, the immunopathologic mechanisms include inflammatory cells and chemical mediators; persistent inflammation develops a local autoimmune, the presence of autoantibodies against extracellular matrix components, ANCA, anti-DNA was detected. Objetives: To determine the presence of auto-antibodies in severe periodontyti. Methods: Ten patients with sever periodontytis were clinically evaluated and 20 healthy people, blood sample was collected to set up IFI for ANCA, antiepithelial antibodies, ANA in Hep2 cells and Western Blot to determine the molecular profile using leucocite and keratynocytes extracts. Results: 57% were positives for ANCA, the total of sera were positives for nuclear and/or cytoplasmic antibodies and 57% presented anti-epithelial antibodies, the sera recognized proteins in a range of molecular weight 10, 30, and 70 kD in leucocyte extract, and 30 and 70 kD in mouse skin extract, mostly in the range of the Hsp family. Conclusions: The nature of the immune response in periodontal disease is influenced by the microflora, however the production of antibodies against self estructures, could be involved in the pathogenic mechanism; these autoantibodies could be associated with necrotic or apoptotic phenomena.Struchture and metabolic activity of microorganism should be involved in mimetic or cross reactions, the antigen procesesing in situ could be eventually stimulate self reactive lymphocytes.
Deficient virus specific IgA production following murine gammaherpesvirus 68 infection of the respiratory tract (48.9)
Authors: Sundararajan Aarthi , Huan Lifang , Joo Hyemee , Speck Samuel , Sangster Mark 
Published: January 2023

Abstract
The B cell response to viruses that replicate in the respiratory tract typically includes an IgA component. Murine gammaherpesvirus 68 (MHV68)infection in the mouse provides a model for studying gammaherpesvirus immunobiology. Following intranasal (i.n.)infection, infectious MHV-68 is cleared from the lung, but the virus establishes latency in B cells, macrophages and dendritic cells. Reactivation of latent virus and shedding in secretions may be critical for virus transmission. The respiratory mucosa is central to MHV68 pathogenesis, but little is known about B cell-mediated mucosal immunity to the virus. We have analyzed this using ELISPOT assay and ELISA to measure antibody secreting cell(ASC)numbers and antibody(Ab)levels, respectively. Although the virus generated a vigorous IgG response in draining lymph nodes, there was little, if any IgA production. In addition, virus-specific IgA was absent from serum and mucosal surfaces of the upper and lower respiratory tract. IgA was prominent in the response to i.n. immunization with inactivated MHV68, indicating that factors associated with virus replication modulate IgA response. Analysis of an MHV68 mutant did not identify genes that may down-regulate IgA production. An IgA response in IFNγR-/- mice following i.n. MHV68 infection indicated a role for strong Th1 type environment in reducing IgA production. Down-regulation of IgA production by MHV68 may reflect a high level of viral adaptation that favors virus transmission.
Nuclear factor-κB drives the development of Foxp3+ regulatory T cells through the c-Rel enhanceosome (49.1)
Authors: Ruan Qingguo , Kameswaran Vasumathi , Tone Yukiko , Li Li , Liou Hsiou-Chi , Greene Mark , Tone Masahide , Chen Youhai 
Published: January 2023

Abstract
Regulatory T (Treg) cells are essential for maintaining immune homeostasis and preventing autoimmune diseases. Although Foxp3 expression marks the commitment of progenitors to Treg cell lineage, how Treg cells are generated during lymphocyte development remains enigmatic. We report here that two members of the nuclear factor (NF)-κB family, i.e., c-Rel and p65 (also known as RelA), controlled the development of Treg cells by promoting the formation of a Foxp3-specific enhanceosome. This enhanceosome contained c-Rel, p65, NFAT, Smad, and CREB. Although Smad and CREB first bound to Foxp3 enhancers, they later moved to the promoter to form the c-Rel enhanceosome. c-Rel-deficient mice had up to 90% reductions of Treg cells compared to wild-type mice, and c-Rel-deficient T cells were compromised in Treg cell differentiation. Thus, Treg cell development is controlled by a Foxp3-specific enhanceosome, and strategies targeting NF-κB can be effective for manipulating Treg cell function.
The Transcriptional Repressor BCL6 Controls the Suppressive Function of Regulatory T cells and Inhibits Th2 Cytokine Expression by Regulatory T cells (49.10)
Authors: Dent Alexander , Sawant Deepali 
Published: January 2023

Abstract
Regulatory T cells (Tregs) expressing the transcription factor FOXP3 represent a distinct lineage of T helper cells indispensable for the maintenance of immune homeostasis and the inhibition of autoimmunity. The transcriptional repressor protein BCL6 critically regulates the immune response. BCL6-deficient mice develop severe and spontaneous inflammation early in life that is frequently lethal. BCL6 is a potent inhibitor of Th2 cell differentiation and is required for differentiation into the follicular helper lineage. However, the role of BCL6 in other T cell subsets is less clear, and little is known about the role of BCL6 in Treg cells despite the fact that BCL6 is an inhibitor of inflammation. We have found that BCL6 is an important regulator of Treg gene expression and function. BCL6-deficient Tregs are hyper-proliferative, are prone towards Th2 cytokine expression and do not suppress inflammation in vivo. Our data indicate that BCL6 is a key inhibitor of Th2 cytokine expression in Treg cells, and that lack of BCL6 activity in Treg cells can lead to abnormal Th2-type inflammatory responses.
Control of Treg by TNFRSF25 (49.12)
Authors: Wolf Dietlinde , Schreiber Taylor , Deyev Vadim , Tsai Matthew , Podack Eckhard 
Published: January 2023

Abstract
TNF-receptor superfamily member 25 (TNFRSF25, DR3), as a member of the TNF receptor superfamily, is constitutively expressed on CD4+ T cells at low levels and upregulated after activation. Signaling through TNFRSF25 enhances Th2 and Th17 cytokine production and contributes to the pathology of several autoimmune diseases. Here we investigate the role of TNFRSF25 on CD4+FoxP3+ Treg cells, where it is constitutively expressed at high levels. We show that TNFRSF25 is unique among several TNFRSF members in its ability to expand Treg in vivo to 30-35% of CD4+ T cells. For TNFRSF25 signaling we use an agonistic α-TNFRSF25 antibody, clone 4C12. The expansion of CD4+FoxP3+ cells is due to increased proliferation of CD4+FoxP3+CD25int cells that express high levels of GITR and CD103. 4C12 expanded CD4+FoxP3+ cells retain TGFβ-dependent suppressive activity ex vivo, except in the continued presence of 4C12. Furthermore, 4C12 rescued TL1A-/- mice from susceptibility to dextran sodium sulfate induced colitis. These data highlight the plasticity of the CD4+FoxP3+ regulatory T cell pool and provide first evidence of a physiological pathway leading to Treg-specific expansion in vivo. Therefore, using TNFRSF25 agonists to modulate Treg function may have important applications for the treatment of autoimmune diseases, chronic infection, transplantation and cancer.
CD4+ T cells expressing VEGFR1 (Vascular Endothelial Growth Factor Receptor1) (49.23)
Authors: Shin Jin-Young , Lim Jong-Hyoung , Cho Hyoung-Soo , Park Chung-Gyu 
Published: January 2023

Abstract
Regulatory T cells are a specialized subpopulation of T cells that control immune response and thereby maintain immune system homeostasis and tolerance to self-antigens. The isolation and expansion of CD4+ Treg cells requires specific surface markers. Currently, CD25, CTLA-4 and GITR are used, but they are also expressed on the activated T cells. In this study, we identified vascular endothelial growth factor receptor 1 (VEGFR1) as a new surface marker for CD4+ regulatory T cells. We found that VEGFR1, a receptor for VEGF involved in angiogenesis, is constitutively expressed on the surface of T cells. CD4+VEGFR1high T cells (1.0 % ± 0.5% of CD4+ T cells) are hyporesponsive and can suppress CD4+ responder T cell (Tres) proliferation as efficiently as CD4+CD25+ regulatory T cells (Treg cells). VEGFR1highCD4+ T cells are also able to mediate potent suppression of Tres in a contact-independent manner. CD4+ VEGFR1high T cells are not overlapped with CD4+Foxp3+ or CD4+CD25+ T cells and secrete IL-10. We suggest that VEGFR1 can be a useful surface marker for CD4+ regulatory T cells and CD4+ VEGFR1high T cells can be a new subset of regulatory T cells.
T cell epitopes (Tregitopes) Suppress Immune Responses in vivo by Activating Natural Tregs (49.24)
Authors: Su Yan , Moise Leonard , Li Xin , Rossi Robert , Skupsky Jonathan , Martin William , DeGroot Annie , Scott David 
Published: January 2023

Abstract
A set of putative natural T regulatory epitopes (Tregitopes, derived from IgG) have been identified, which have suppressive effects both in vitro and in vivo. These Tregitopes are promiscuous, bind highly to MHC class II and are highly conserved in multiple species. In this study, we further investigated the mechanisms of suppression by Tregitopes. We first demonstrated that neither CFA nor IFA emulsified Tregitopes peptides per se are immunogenic in vivo. Administration of Tregitopes by IFA upregulated FoxP3+ T cells and reduced specific CD4+ T cell responses in OVA TCR transgenic and normal Balb/c mice. Interestingly, we found that Tregitopes activated natural, but not inducible Tregs. Furthermore, B cells that are pulsed with Tregitopes and a target antigen OVA in vitro acquired tolerogenic phenotypes. These B cells can suppress both T cell and antibody responses to OVA protein in vivo. In NOD mice, administration of Tregitopes resulted in delayed onset of type I diabetes and even reversed hyperglycemia in the majority of new onset diabetic mice. Together, our results suggest that Tregs induced by Tregitopes represents a new paradigm for treatment of autoimmune disease (Supported by NIH grants RO1 AI035622, RO1 DK068343 and R43 DK081261).
Antigen dose differentially controls the induction of specific Treg and Teff populations (49.5)
Authors: Turner Michael , Morel Penelope 
Published: January 2023

Abstract
The concept that Th1/Th2 differentiation may be affected by antigen dose was introduced a decade ago (O’Garra, Bottomly). Recently, we reported that antigen dose also controls Treg induction whereby low antigen doses elicit weak signals via the TCR/Akt/mTOR pathway, allowing Foxp3 expression and expansion of Treg. METHODS: We expanded our studies on antigen dose effects to include regulatory and effector populations that have been recently added to the CD4+ repertoire. Purified CD4+ T cells from BDC2.5 TCR transgenic mice were stimulated by DC pulsed with increasing doses of peptide antigen. After 7 days of priming, T cells were re-stimulated with anti-CD3 and anti-CD28 and analyzed for cytokine production and Foxp3 expression. RESULTS: We found that altering the antigen dose qualitatively affected the CD4+ T cell response in a hierarchical manner. Low dose stimulation led to Foxp3+ Treg expansion; intermediate doses induced IL-13+ Th2 and IL-10+ Tr1 cells; and higher antigen doses favored Th1/Th17 responses. In addition, when low-dose-stimulated T cells were subsequently re-stimulated with a high antigen dose, the Th1/Th17 response remained diminished. CONCLUSIONS: Our results indicate that Tr1, Th17 and Treg are included in the repertoire of CD4+ T cells that are affected by antigen dose. These findings have broad implications for vaccine design and we are in the process of determining the in vivo significance of these qualitative changes to the CD4 compartment.
In vivo administration of mitogenic anti-CD3 monoclonal antibody generates granzyme B expressing CD4+Foxp3+ regulatory T cells and depletes dendritic cells (49.6)
Authors: Suvas Susmit , Vietto Nicholas , Channappanavar Rudragouda , Twardy Brandon 
Published: January 2023

Abstract
CD3 specific monoclonal antibody therapy uses multiple mechanisms to induce immune tolerance. In this report, we determined that intra-peritoneal administration of 10 µg of mitogenic anti-CD3 monoclonal antibody (mAb) into C57BL/6 mice resulted in a significant reduction in the frequency of splenic dendritic cells (CD11chi) when compared to PBS treated mice at 24h post-injection. Interestingly, the proportion of CD11chi cells undergoing apoptosis (as determined by Apo-stat assay) was significantly higher in anti-CD3 treated mice in comparison to PBS treated control group. Recently, it was shown that in vitro activation of CD4+CD25+ regulatory T cells with anti-CD3 mAb induces granzyme B expression in regulatory T cells and transforms them into cytolytic T cells. To determine the underlying mechanism of increased apoptosis of dendritic cells in anti-CD3 mAb treated mice, we next ascertained the expression of granzyme B in CD4+Foxp3+ regulatory T cells (Treg) derived from the spleen tissue of anti-CD3 and PBS treated groups of mice. Our results showed that when restimulated in vitro with anti-CD3 mAb (1 µg/ml) for 6h, frequency of Treg expressing cell surface CD107a and intracellular granzyme B was significantly higher in anti-CD3 treated mice in comparison to PBS treated control group. Taken together, our results determined that in vivo administration of anti-CD3 mAb resulted in the induction of granzyme B expressing Treg pool and enhanced apoptosis of dendritic cells.
β-catenin inhibits T cell activation by selective interference with LAT-PLC-γ1 phosphorylation. (50.12)
Authors: Gajewski Thomas , Zheng Yan , Locke Frederick , Cannon Judy , Gounari Fotini , Driessens Gregory 
Published: January 2023

Abstract
The functional role of β-catenin in post-thymic T cells is poorly understood. We observed that β-catenin protein was constitutively degraded in peripheral T cells. Introduction of a stabilized mutant of β-catenin into primary T cells resulted in reduced proliferation and cytokine secretion following TCR/CD28 stimulation, and interfered with effector cell differentation. The biochemical mechanism of blunted T cell activation was investigated. Stable β-catenin was predominantly localized to the cytosol, and cytokine production was rescued with PMA+Ionomycin, arguing for an inhibitory effect on early TCR signaling. Analysis of specific signaling events revealed a selective inhibition of LAT phosphorylation on tyrosine 136, which was associated with defective PLC-γ1 phosphorylation and calcium signaling but normal ERK activation. Stable β-catenin was detected constitutively in regulatory T cells, and conditional deletion of β-catenin in these cells caused rapid cell death. Contrary to a recent report using GSK-3 inhibitors, we saw no effect on T cell memory differentiation with direct genetic manipulation of β-catenin. Our findings indicate that β-catenin negatively regulates effector T cell activation via a unique biochemical mechanism. Functionally, our observations suggest that conditions under which β-catenin might be inhibited in vivo would potentiate T cell-based immunity at the level of both effector and regulatory T cells.
Regulation of TCR signaling and CARD11 by the kinesin GAKIN (50.16)
Authors: Lamason Rebecca , Kupfer Abraham , Pomerantz Joel 
Published: January 2023

Abstract
Lymphocyte signaling from the T cell receptor (TCR) to NF-κB is required for mounting an appropriate immune response and is regulated at multiple steps. One such regulatory mechanism involves the activation and synapse recruitment of protein signaling complexes, including one that contains CARD11, a multi-domain scaffold protein required for TCR signaling to NF-κB. To identify novel regulators of CARD11, we conducted an expression-cloning screen that yielded the kinesin family member, guanylate kinase-associated kinesin (GAKIN). We show that GAKIN is a novel inhibitor of NF-κB activation that can interact with CARD11 in a signal dependent manner, can compete with Bcl10 for CARD11 association, and may regulate the dynamic localization of CARD11 to the immunological synapse. This study indentifies GAKIN as a novel component of the TCR to NF-κB pathway and reveals a previously unrecognized mechanism for controlling the strength or duration of T cell signaling.
Persistent Changes in T Cell Receptor Surface Organization Visualized by Quantum Dot Probes with k-Space Image Correlation Spectroscopy (50.2)
Authors: Perica Karlo , Bieler Joan , Li Yu , Selya Aaron , Edidin Michael , Schneck Jonathan 
Published: January 2023

Abstract
There is growing evidence that the surface pattern and spatial distribution of T cell receptors (TCRs) on cell surfaces plays a critical role in T Cell antigen detection and effector function, from micron-sized Supramolecular Adhesion Clusters to microclusters 100’s of nanometers in diameter. To date, TCR organization patterns have been primarily examined in the context of antigen stimulation or immediately thereafter, on a timescale of seconds to minutes, despite evidence from binding studies that shows changes persist many days post-activation. Here, we present a method for imaging long-term TCR lateral surface organization on live cells at two relevant length scales: 10’s and 100’s of nms. TCR are labeled with monomeric biotin-MHC/peptide or antibody fragments, followed by streptavidin-quantum dots (QD). We have found that QD “blinking” is a useful parameter for detecting TCR organization on a nm scale, since electronic coupling between blinking states of adjacent QDs reports single or small clusters of receptors. Simultaneously, we quantify organization at the scale of 100’s of nms by epifluorescense. As proof of principle, we have demonstrated that in vitro activated T cells have enhanced clustering at the 10’s and 100’s nm scales compared to naïve counterparts, supporting results from MHC dimer binding assays. Clustering can also be modulated by IL-2 signaling for active, but not naïve, T cells.