bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic and pharmaceutical targeting of OCA-B/Pou2af1 blocks T1D in mouse models
Authors: Kim Heejoo , Shakya Arvind , Perovanovic Jelena , Ibarra Andrea , Evavold Brian , Chou Danny H.-C. , He Xiao , Jensen Peter E , Tantin Dean R 
Published: January 2023

Abstract
Treatments for autoimmunity aim to inhibit autoreactivity while preserving normal immune function. The transcriptional coregulator OCA-B (gene symbol Pou2af1) is induced in stimulated naïve CD4+ T cells, where docks with transcription factor Oct1 to regulate genes such as Il2 and Ifng. Oct1 and OCA-B only regulate their targets in cases of persistent antigen exposure, a common feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion would protect mice from autoimmune diabetes, and that pharmacologic OCA-B inhibition would similarly protect diabetes-prone mice. We generated an Ocab (Pou2af1) conditional allele onto a NOD/ShiLtJ strain background. OCA-B loss in T cells had no effect on the naïve T cell receptor repertoire or gene expression in the pancreatic lymph nodes, but protected NOD mice from both mice spontaneous and induced T1D. In scRNA-seq data with pancreatic leukocytes, dominant CD8 TCR clones known to participate in disease failed to emerge in the islets of OCA-B deficient mice. Protection was also associated with reduced islet neutrophil and macrophage infiltration and reduced neutrophil activation. The protective effect of OCA-B loss was diminished, or even eliminated, using monoclonal TCR models with high affinity to artificial or neoantigens. Finally, we developed rationally-designed membrane-penetrating peptide inhibitors of the interaction between OCA-B and its downstream target, Jmjd1a. Pharmacologic OCA-B inhibition normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression, in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.
Lupus susceptibility gene Pbx1 promotes atherosclerosis via dysfunctional T cells in a mouse model
Authors: Li Wei , Elshikha Ahmed , Teng Xiangyu , Abboud Georges , Brown Josephine Michelle , Choi Seung-Chul , Fredenburg Kristianna , Major Amy S , Morel Laurence 
Published: January 2023

Abstract
The incidence of atherosclerosis is higher among patients with systemic lupus erythematosus (SLE). An imbalance between regulatory T cells (Treg) and follicular helper T cells (Tfh) occurs in the development and progression in both diseases. However, the mechanisms by which lupus T cells may aggravate atherosclerosis remain unclear. Pre-B-cell leukemia transcription factor 1 isoform d (Pbx1-d) is a lupus susceptibility gene and transgenic (Tg) Pbx1-d in CD4+ T cells expands Tfh and impairs Treg. Here, we investigated the role of CD4-Pbx1-d-Tg T cells in the low-density lipoprotein receptor-deficient (Ldlr−/−) mice, an experimental model for atherosclerosis. Pbx1-d T cells exacerbated atherosclerosis in Ldlr−/− mice as compared to B6 T cells. The enhanced atherosclerosis was associated with increased body weight, increased autoantibody production, reduced Treg in the aorta, as well as increased splenic Tfh frequency and impaired Treg cell suppressive markers. Dyslipidemia inhibited the differentiation and function of Treg cells in vitro. Moreover, Pbx1-d Treg cells were less suppressive than B6 control Treg cells in dyslipidemia conditions. Thus, our results showed that Pbx1-d-Tg T cells exacerbate atherosclerosis due to the dysregulated Treg and Tfh cells, briging autoimmunity and cardiovascular pathology.
Investigating the antigen-specific T cell response to MHC variant peptide 45D
Authors: Faust Michael A , Kolawole Elizabeth , Evavold Brian 
Published: January 2023

Abstract
We have previously generated a variant of the myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide by mutation of the P6 MHC anchor residue from an S to a D amino acid. Here, we confirm previous findings that the 45D MHC variant peptide is incapable of inducing experimental autoimmune encephalomyelitis (EAE) despite its CD4 epitope bearing the same TCR contact residues as wildtype MOG epitope (wtMOG). Using the micropipette adhesion frequency assay (MP), we show that induction with 45D generates reduced levels of CD4 T cells specific for MOG in the CNS but not the periphery of asymptomatic mice. Importantly, 45D induction results in a loss of high affinity CD4 T cells, which could be responsible for initiation of disease. We also found changes in MOG-reactivity within the peripheral Treg compartment of 45D-induced mice. Together, the variant peptide alters the MOG-specific Teff and Treg response. Although the 45D mutation was designed to target the CD4 MOG epitope, it also changes the antigen responsible for expanding MOG-reactive CD8 T cells. We find that priming with 45D expands CD8 T cells with heightened affinity for MOG. Taken together, our data demonstrate that 45D may enhance peripheral tolerance mechanisms that ultimately aid in the protection from autoimmune disease.
Differential effects of Flavipin on Ahr and Arid5a: A new therapeutic strategy for autoimmune encephalomyelitis
Authors: Hanieh Hamza N , Alzahrani Abdulllah 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a World-wide spread autoimmune disease that includes episode of demyelination in the central nervous system (CNS). Accumulating evidence has demonstrated that ligand-activated aryl hydrocarbon receptor (Ahr) improves pathological outcomes in experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Recent evidences have shown that AT-rich interactive domain-containing protein 5a (Arid5a), an RNA-binding protein, is required for development of EAE via stabilizing the mRNAs of interleukin-6 (Il6) and Ox40. To date, there are no reports studying both Ahr and Arid5a as a potential therapeutic strategy for MS. Thus, current work applied in silico, in vitro and in vivo approaches to identify a molecule that interacts with Ahr and Arid5a. The results identified Flavipin (3,4,5-trihydroxy-6-methylphthalaldehyde) as a new Ahr agonist that induces the expression of downstream genes in mice CD4+ T cells and CD11b+ macrophages. Interestingly, Flavipin inhibited the stabilizing function of Arid5a, and impaired its counteracting effects on RNase function of Regnase-1 on 3′ untranslated region (3′UTR) of Il6, Ox40 and signal transducer and activator of transcription 3 (stat3). In EAE, Flavipin ameliorated disease symptoms concomitant with inducing acetylcholinesterase (AChE)-targeting miR-132. It reduced the expression of Ox40 in CD4+ T cells and the number infiltrated CD4+CD45+ T cells in the CNS. Further analysis identified Il23a mRNA as a new target for Arid5a. Taken together, our findings provide first evidences on differential effects of Flavipin on Ahr and Arid5a and pave an avenue for a new therapeutic strategy for autoimmune diseases such as MS.
TNF-α orchestrates CD4+ T cell-dependent inflammation via TNFR2 signaling
Authors: Alam Muhammad S 
Published: January 2023

Abstract
CD4+ T helper subsets, in particular Th1 and Th17, produce cytokines that play critical roles in inflammatory diseases. TNF-α, produced largely by innate immune cells, is also potently pro-inflammatory. Here we asked if TNF-α contributes to effector CD4+ Th generation, and found that in the presence of TGF-β TNF-α signals via its non-death receptor TNFR2 to generate Th17 cells expressing inflammatory mediators such as GM-CSF, CXCL3, and IFN-γ. Single cell RNA-Seq of CNS-infiltrating CD4+ T cells in EAE identified an IL-17-positive cluster with an inflammatory gene signature that required TNFR2 expression. Notably, TNFR2-deficient CD4+ T cells produced fewer inflammatory mediators and were relatively nonpathogenic in EAE and colitis. Thus, TNF-α is not just an effector but also an initiator of Th differentiation, raising the possibility that in diseases in which both TNF-α and IL-17 contribute, targeting TNF-α may diminish the generation of pathogenic Th17 cells.
Aberrant expression of β5t in the periphery induces a self-reactive T-cell response
Authors: Tomaru Utano , Kimoto Rikuto , Ishizu Akihiro , Kasahara Masanori 
Published: January 2023

Abstract
The thymoproteasome subunit β5t is specifically expressed in cortical thymic epithelial cells (cTECs) and generates unique peptides to support positive selection. However, in the context of systemic immune homeostasis, it remains unclear why the expression of β5t-containing proteasomes is restricted to the thymus. In this study, using a mouse model ubiquitously expressing β5t (β5i−/−β5t-Tg), we showed that the aberrant peripheral expression of self-peptides generated by β5t affects the peripheral naïve pool of CD8+ T cells. In β5i−/−β5t-Tg mice, the percentage of naïve CD44lowCD122lowwas reduced, and the percentage of memory CD44highCD122high CD8+ T cells was significantly elevated. When naïve CD44lowCD122low CD8+ T cells from EGFP mice, which exhibited the wild type (WT) phenotype and underwent thymic selection by β5t-expressing cTECs, were transferred into β5i−/−β5t-Tg, transferred cells changed their phenotype from CD44lowCD122low to CD44highCD122high. The transferred EGFP+ CD8+ T cells with a CD44highCD122high phenotype showed increased expression of PD-1 and Tim-3, and these alterations were affected by the condition of peripheral antigen-presenting cells in β5i−/−β5t-Tg recipient mice. The transferred CD8+ T cells from WT mice caused chronic inflammation in β5i−/−β5t-Tg recipient mice. These results demonstrate that the aberrant peripheral expression of β5t disrupts the maintenance of a naïve pool of CD8+ T cells and induces autoreactive T-cell responses. The self-peptides generated by β5t are required to confine in the thymus to avoid autoimmunity in the peripheral tissues, and self-peptides mimicking β5t-producing peptides in the periphery may cause the failure of immunological regulation and tolerance.
More roles of IL-4 than being as an antagonist of IFN-γ in experimental autoimmune uveitis
Authors: Shen Chia-Rui , Yang Wei-Cheng , Hwang Yih-Shiou , Hong Wei-Hsin , Liu Chao-Lin 
Published: January 2023

Abstract
IL-4 appears to be beneficial for some autoimmune diseases. Despite its role in antagonizing pathogenic Th1 response, our recent work has demonstrated IL-4 possesses functions affecting the regulatory T (Treg) cells. Here we aimed to identify the role of IL-4 in the development of experimental autoimmune uveitis (EAU). EAU was induced in WT and IL-4 KO mice via active interphotoreceptor retinoid binding protein (IRBP) immunization, and the disease development was monitored by funduscopic and histology analysis as well as the IRBP-specific immune responses by flow cytometric analysis and ELISA. It showed that the onset of disease, if the clinical score equals to 1, was day 14 and 20 in IL-4KO and WT mice, respectively. The fundoscopic images demonstrated the more and bigger size of lesions, increased leukocyte infiltration, vasculitis and neovascularization in IL-4KO mice. The histological analysis also confirmed the mononuclear cell infiltration. Moreover, Th1 effector is known as the dominant pathogenic mediators, whereas Treg cells play an important and indispensable role in control of EAU progression and disease remission. The splenic T cells from IL-4 KO EAU animals produced significantly elevated level of IFN-γ in responding to IRBP stimulation. However, there seems no significant but some alternation in the presence of Treg cells (Foxp3+) among CD4+CD25+ T cells in the spleens and lymph nodes of IL-4 KO and WT mice. These results demonstrate the lack of IL-4 disrupting the induction of EAU and leading to an increased disease severity through not only antagonizing IFN-γ but also involved mechanisms of immune-regulation. Therefore, IL-4 might play more roles than being just an antagonist of IFN-γ in autoimmune uveitis.
A Direct Link between IL-17 and Regulatory T cells in Autoimmune Colitis
Authors: Pitmon Elise V , Chen Ju , Ye Xiaoyang , Wang Kepeng 
Published: January 2023

Abstract
Inflammatory bowel diseases are rising in prevalence globally. While current treatments aim to achieve remission, there remains no cure for this disease. IL-17 family cytokines are important players in inflammation, but clinical trials using anti-IL-17A or IL-17RA blocking antibodies have failed for Crohn’s disease, due to exacerbated inflammation in some patients. While anti-IL-17 antibodies have shown efficacy in the treatment of other autoimmune diseases like psoriasis, patients can often develop Crohn’s disease as a side effect of these drugs. These data suggest a protective role of IL-17 in gut inflammation. The proper activation and function of regulatory T cells is essential for the protection against intestinal autoimmune inflammation. Using the naïve T cell transfer model of colitis in mice, we found that IL-17RA-null iTregs, transferred after the establishment of colitis, were less effective at controlling the colitis compared to WT iTregs. Naïve T cells cultured ex vivo in iTreg polarizing conditions had an increase in complete iTreg differentiation when stimulated with IL-17 cytokines. Our results indicate that IL-17 directly signals to Tregs and assists their anti-inflammatory role during autoimmune gut inflammation. Although the underlying mechanism remains under study, this finding suggests an inhibitory loop between IL-17 and Tregs for the control of overt inflammation.
Melanocyte-specific CD8+ T cells demonstrate tolerance characterized by an impaired ability to differentiate into a highly proliferative population
Authors: Truckenbrod Emily Nestor , Renkema Kristin R , Burrack Kristina S , da Silva Henrique Borges , Jameson Stephen C 
Published: January 2023

Abstract
The mechanisms governing non-deletional CD8+ T cell tolerance are poorly understood. We are using a physiologically-relevant mouse model to better understand the regulation of self-specific CD8+ T cells, which impact both autoimmune disease and cancer. We find a substantial number of polyclonal cells specific for an epitope from the melanocyte/melanoma-associated enzyme tyrosinase-related protein 2 (Trp2) in both wild-type (WT) C57BL/6 and Trp2-deficient (Trp2 KO) mice. In pre-immune mice, these cells have a naïve phenotype in both strains, and they respond similarly for the first several days after in vivo stimulation with Trp2 peptide alone or in combination with adjuvants (TriVax). However, significantly fewer WT Trp2-specific cells are present at an effector timepoint after TriVax or recombinant Trp2-expressing Listeria monocytogenes relative to KO Trp2-specific cells. WT Trp2-specific cells also show a deficiency in mediating vitiligo compared with KO cells when TriVax-generated effectors are transferred into recipient WT mice primed with TriVax and dinitrofluorobenzene (DNFB). Single-cell RNA sequencing at day three after stimulation reveals that KO Trp2-specific cells efficiently differentiate into a proliferative population, whereas few WT Trp2-specific cells demonstrate this phenotype. As a population, WT Trp2-specific CD8+ T cells exhibit covert anergy: despite a naïve appearance at steady state and initial acquisition of activation markers after stimulation, these self-specific cells are unable to expand productively or to efficiently mediate functional anti-melanocyte activity. These findings have implications for recently-described non-deletional CD8+ T cell tolerance in humans.
Somatostatin receptor subtype 4 protects against indomethacin-induced gastrointestinal mucosal injury in mouse
Authors: Cseko Kata , Kormos Viktória , Horváth Ádám István , Kecskés Angéla , Gaszner Balázs , Sudalina Maria , Iarushkina Natalia , Zelena Dóra , Filaretova Ludmila , Helyes Zsuzsanna 
Published: January 2023

Abstract
Despite recent advancements in the pharmacologic and endoscopic management of gastrointestinal ulceration, it is still associated with high mortality. Therefore, it is important to understand mucosal protective mechanisms. Somatostatin, present in the endocrine cells & sensory nerves, and its analogues reduce mucosal blood flow, pepsin and gastric acid secretion. Its receptor subtype 4 (sst4) mediates anti-inflammatory & analgesic actions, as discovered by our group. Therefore, our aim was to investigate its role in gastrointestinal injury.
We treated sst4 gene-deleted (sst4−/−) and wildtype mice with indomethacine (IDM; 35 mg/kg) or vehicle s.c.. Gastric & small intestine lesions were evaluated after 4 & 48 h macroscopically & microscopically. Plasma protein extravasation & myeloperoxidase (MPO) activity were assessed by ex vivo imaging, TNFα, IL-1, COX2, sst4 & somatostatin mRNA levels by qPCR.
Gastric (4h) and small intestinal macroscopic (24 h) lesions, MPO activity (24, 48 h), and plasma extravasation (30 min) were significantly greater in IDM-treated sst4−/− mice, while histopathological scores & small intestinal length did not show strain difference. TNFα, IL-1, COX2 significantly upregulated after 4h in the stomach of sst4−/− mice, and the same pattern was observable in wildtype mice at later timepoint (48 h).
These results provide evidence for the protective role of the sst4 receptor against IDM-induced gastrointestinal mucosal injury. This suggests the safety of sst4 agonist drug candidates in the gastrointestinal tract, and even their potential use for gastroprotective indication.
Supported by: GINOP-2.3.2-15-2016-00050 – PEPSYS, GINOP-2.3.2 STAY ALIVE, EFOP-3.6.2-16-2017-00008, ÚNKP-19-3-III-PTE-211
Increased neuroinflammation and atherosclerosis in sleep fragmented mice
Authors: Moriarty Alina K , Keeter W. Coles , Waseem Tayab , Ma Shelby , Gauronskas Phillip Joseph , Butcher Matthew J , Wellman Laurie , Sanford Larry , Galkina Elena 
Published: January 2023

Abstract
There are roughly 70 million Americans who report insufficient sleep due to work responsibilities, sleep apnea, or lifestyle choices. Altered duration and poor sleep quality are associated with an increase in brain inflammation, high rates of cardiovascular disease and other inflammatory diseases in humans. It is known that psychological stress is associated with increased atherogenesis, it is also known that sleep fragmentation (SF) can exacerbate and be induced by SF. However, the exact relationship between SF, neuroinflammation, and atherogenesis is not well known. We found that chronic SF led to increased plaque formation in the aortas HFD fed Apoe−/− mice. SF also resulted in alterations in the immune composition of the bone marrow (BM), blood, aortas, and lymph nodes in the HFD fed Apoe−/− mice. Importantly we detected an increased content of myeloid cells in the blood of SF and HFD fed female Apoe−/− mice. There was an increased percentage of CD68+ macrophages in SF Apoe−/− aortas. Additionally, we detected an increase in CD11b expression and inflammatory markers in the brains of mice that were sleep fragmented when compared to control mice. Our data suggest that SF induces elevated myelopoeisis resulting in monocytosis, neutrophilia, and the altered immune composition of the aortas of atherosclerosis-prone mice, resulting in accelerated atherosclerotic plaque burden.
Progressive immunosenescence in diabetic chronic kidney disease
Authors: Hong Ruo-Wei , Shu Kai-Hsiang , Chen I-Yu , Lay Fang-Yun , Chuang Yi-Fang , Chiu Yen-Ling 
Published: January 2023

Abstract
Type 2 diabetes is an important challenge given the worldwide epidemic and is the most important cause of end-stage renal disease in developed countries. It is known that patients with end-stage renal disease and advanced renal failure suffer from immunosenescence and premature T cell aging, but whether such changes develop in patients with less severe chronic kidney disease (CKD) is unclear. We investigated level of immunosenescence in 770 Patients with type 2 diabetes with different levels of renal function. Consistent with previous observations in the general population, both T and monocyte immunosenescence in diabetic patients positively correlate with age. Compared to patients with eGFR&gt;60 ml/min, patients with more severe CKD showed a progressive decrease in total CD3+ T cells, but not in monocyte numbers. Immunosenescence, as defined by multiple phenotypic markers, was significantly upregulated in both CKD stage 3 and stage 4/5 patients, especially of CD8+ T cells. In age and sex-adjusted regression models, stage 3 CKD patients exhibited significantly elevated percentages of CD28−, CD127−, and CD57+ cells among CD8+ T cells when compared to patients with eGFR&gt;60 ml/min. In contrast, no change was detected in monocyte subpopulations as renal function declined. Our study indicates that therapeutic approaches to prevent the emergence of immunosenescence in renal failure patients should be implanted before stage 3 CKD.
A circulating population of CD4+ cutaneous resident memory T cells is diminished in humans with fibrotic disease
Authors: Morawski Peter A , Fahning Mitch , Varkhande Suraj , Beale Emma , Klicznik Maria , Gratz Iris , Campbell Daniel J. 
Published: January 2023

Abstract
Tissue-resident memory T cells (TRM) persist mainly in non-lymphoid tissues where they promote immune recall responses to recurrent insults. We previously defined a population of CD4+CD103+ TRM cells from human skin that become CD69neg and re-enter the circulation, but maintain expression of the skin-associated marker cutaneous lymphocyte antigen (CLA) and the capacity to return to the skin. Comparing blood- and skin-derived CLA+ memory populations, we found that the recirculating fraction of CD103+ TRM are clonally, transcriptionally, and phenotypically most similar to skin-resident CD103+ T cells. We now report that the circulating CD4+CLA+CD103+ T cells are functionally distinct from classically-defined CD4+ T helper lineages, highlighted by the co-production of IL-22 and IL-13. As these cytokines can promote tissue repair macrophage- and epithelial cell-mediated fibrosis and wound healing, we assessed the circulating skin TRM pool during systemic scleroderma (SSc), an autoimmune disorder highlighted by fibrosis of the skin and the underlying organs. Compared to healthy donors, SSc patients had a reduced frequency of circulating CD4+CLA+CD103+ T cells with diminished per-cell IL-13 production, both of which correlated with late-onset disease. Our ongoing work aims to understand how changes in the circulating TRM fraction might be a litmus for the onset or progression of SSc and similar skin diseases. Therefore, circulating CD4+CLA+CD103+ T cells represent a broadly available pool from which the isolation and study of skin TRM cell responses is possible both in health and disease.