bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oct1 and OCA-B in T cells are potent therapeutic targets for autoimmune diseases
Authors: Kim Heejoo , Shakya Arvind , Dickey Laura , Stone Colleen , Lane Thomas , Williams Matthew A , Tantin Dean R 
Published: January 2023

Abstract
Oct1 and OCA-B function together in CD4 T cells to promote poised gene expression states in immunomodulatory target genes (e.g. Il2, Il21, Ifng, Icos and Cd25) via the recruitment of the histone lysine demethylase Jmjd1a/Kdm3a. Oct1 and OCA-B are also critical for the generation of functional CD4 memory T cells in response to pathogen infection. Memory T cell phenotypes can promote autoimmunity, even in cases of persistent self-antigen exposure. In GWAS, single nucleotide polymorphisms in Oct1 binding sites for multiple genes are associated with T1D and MS. These findings suggest that Oct1 and OCA-B could modulate autoimmunity. Using a new T cell-specific OCA-B conditional-deleted Non-obese diabetic (NOD) mouse model, we find that T cell specific OCA-B deletion completely protects the animals from T1D. This is associated with reductions in pathogenic, pancreatic-infiltrating T cell numbers and cytokine production. In contrast, pancreatic lymph node T cell function is normal, suggesting that non-self-directed immune function is largely intact. Moreover, we have developed OCA-B inhibitor peptides as novel therapy for T1D and shown these to be efficacious in NOD mice. In EAE, which is a model for MS, Oct1 loss in T cells decreases clinical scores, T cell infiltrate and cytokine production. However, using a JHMV intracranial infection model, Oct1 loss has only minimal effects in clinical scores, viral clearance, infiltrating immune cells and cytokine production. These results suggest a therapeutic window in which deleting these proteins blunts autoimmunity while keeping normal immune function largely intact.
REGULATION OF T FOLLICULAR CELL DEVELOPMENT BY E3 UBIQUITIN LIGASE CBL-B IN SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: tu sha , Tang Rong , Guo Hui , Liu Qing jun , Zhang Jian 
Published: January 2023

Abstract
T follicular helper cells (Tfh) are critical in providing help to B cells, and have been shown to be involved in the overproduction of pathogenic auto-Abs and tissue damage in lupus. Cbl-b, a RING finger E3 ubiquitin ligase, negatively regulates lymphocyte activation. In this study, we found that the expression of Cbl-b in CD4+ T cells from lpr mice on a C57BL/6 background (B6-lpr) was down-regulated. Introducing Cbl-b deficiency or Cbl-b C373A mutation into B6-lpr mice significantly exacerbated the onset of the disease in B6-lpr mice, which correlated with heightened serum auto-antibody titers, exaggerated Tfh, GC B cells, and plasma cells. These data indicate that Cbl-b negatively regulates lupus disease progression and Tfh development via its E3 ubiquitin ligase activity. In support of a critical role of Cbl-b in Tfh development, mice specifically deficient for Cbl-b in T cells also exhibited an increase in Tfh when they were immunized with OVA in CFA. Mechanistically, Cbl-b appeared to specifically bind to Bcl6, and target Bcl-6 for ubiquitination and degradation. In strong support of Cbl-b in exaggerated Tfh in lupus, we found that Tfh cells were increased in the peripheral blood of SLE patients. Furthermore, Cbl-b expression was significantly reduced in Tfh from patient with SLE. Therefore, our data indicate that Cbl-b suppresses Tfh development by targeting Bcl6, and that deregulated expression of Cbl-b may play a crucial in aberrant Tfh development, thus eliciting pathogenic auto-Ab production by B cells.
Single-cell transcriptome analysis reveals diverse islet-infiltrating T cell subsets and a role for BATF in promoting the diabetogenic activity of CD8 T cells
Authors: Ciecko Ashley E , Schauder David M , Foda Bardees M , Lin Chien-Wei , Cui Weiguo , Chen Yi-Guang 
Published: January 2023

Abstract
T cells infiltrate pancreatic islets and directly mediate the destruction of insulin-producing β cells during the development of type 1 diabetes (T1D). However, islet-infiltrating T cell differentiation states and functional diversity have not been completely defined. We used unbiased single-cell RNA sequencing analyses to define the phenotypic complexity of islet-infiltrating T cells in non-obese diabetic (NOD) mice. In the CD4 T cell compartment, we identified naïve, memory, and regulatory T cells, as well as multiple Il21 expressing effector subsets positive for markers indicative of Th1 and Tfh cells. In the CD8 T cell compartment, we identified naïve cells and two activated subsets defined by Slamf6 or Cxcr6 expression, respectively resembling the self-renewing progenitor cells and terminally differentiated effectors found during chronic lymphocytic choriomeningitis virus (LCMV) infection. Single-cell regulatory network inference and clustering (SCENIC) analysis revealed that regulon activity of several transcription factors with known roles in effector CD8 T cell function including Batf were turned on in the Slamf6+ and Cxcr6+ cells. Previous studies have shown that IL-21 induced BATF expression in CD8 T cells is critical to sustain their effector function against chronic LCMV infection. Similarly, we found lower BATF expression in activated islet CD8 T cells from NOD. Il21+/− compared to NOD mice. We further demonstrated that overexpression of BATF in β cell autoreactive CD8 T cells eliminated their need for IL-21 to cause T1D. Our results reveal phenotypically diverse and novel islet-infiltrating T cell subsets and suggest a model in which the IL-21-BATF pathway is critical for the diabetogenic activity of CD8 T cells.
Age-associated changes in central T cell tolerance induction
Authors: Cepeda Sergio , Hester Allison K , Yangming Xiao , Kraig Ellen B , Griffith Ann V 
Published: January 2023

Abstract
Susceptibility to certain autoimmune diseases increases with age; however, mechanisms linking aging and increased susceptibility are incompletely understood. One hallmark of the aging immune system is atrophy of the thymus, the primary site of T lymphocyte generation. We and others have previously shown that aging is also associated with declines in critical thymic functions, including expression of tissue restricted self-antigen (TRA) genes, many of which are regulated by the autoimmune regulator, Aire. TRA expression in the thymus allows T cells to be tolerized to antigens typically expressed in peripheral tissues, and declining TRA expression is predicted to contribute to diminished T cell tolerance in aging. Medullary thymic epithelial cells (mTECs) had been regarded as the sole source of thymic TRA expression, but it is now clear that a subset of thymic B (tB) cells also express Aire and mediate tolerance to Aire-dependent self-antigens. Recently, we found that expression of Aire and Aire-dependent self-antigens declines in tB cells in aged mice and humans, which is also predicted to diminish central T cell tolerance induction. To test these predictions, we used MHCII tetramers to detect T cells recognizing a model TRA expressed in mTECs, Apolipoprotein B (Apob, an auto-antigen involved in atherosclerosis), in the thymus and secondary lymphoid organs of aged mice. We find that the frequency of potentially auto-reactive ApoB-specific T cells increases beginning at 6 months of age. Ongoing experiments will address whether there are similar increases in T cells specific for other TRAs, including Titin (Ttn), an autoantigen involved in late onset myasthenia gravis.
Rab4A inactivation in T cells blocks mTOR activation, pro-inflammatory lineage development, and disease pathogenesis in lupus-prone mice
Authors: Huang Nick , Wyman Brandon , Cravo Emma , Winans Thomas , Choudhary Gourav , Oaks Zachary , Duarte Manuel , Lewis Josh , Lai Zhi-Wei , Banki Katalin , Perl Andras 
Published: January 2023

Abstract

Introduction
Expression of Rab4A is increased in T cells of patients and mice with SLE. Overexpression of Rab4A forms a positive feedback loop with mTOR that can be blocked with therapeutic efficacy in SLE. To determine the impact of this gene on disease development, the triple-congenic lupus-prone Sle1.2.3 mouse strain (TC) have been backcrossed with C57Bl/6 wild-type (WT) mice that carry floxed Rab4AQ72L (TC-FL) alleles or lack Rab4A in T cells (TC-KO).

Methods
Proteinuria was assessed by the Bradford assay. Splenocytes were examined by flow cytometry. Autoantibody production was measured by ELISA.

Results
TC mice had increased proteinuria over age and sex-matched WT controls. Deletion of Rab4A in T cells reduced proteinuria ≥ 50% in female TC-KO mice relative to TC-FL mice at 21 or 40 weeks of age. Similar trends were noted in male mice. The production of antinuclear and antiphospholipid antibodies was reduced in TC-KO mice as compared to TC-FL and parental TC controls.
Immunophenotyping unveiled a 45% depletion of CD4+ T cells and 50% expansion of CD8+ T cells in female TC-KO mice relative to TC-FL controls. CD38 expression was reduced on CD4+ T cells of TC-KO mice by 51% and 48% relative to TC and TC-FL controls. CD38 expression was also reduced on CD8+ T cells but not on CD19+ B cells. mTORC1 activity was reduced by 36% in CD4 T cells, but not in CD8 T cells or B cells of TC-KO mice. Along these lines, overexpression of Rab4A activated mTORC1, reduced expression of CD4, and increased expression of CD38 in Jurkat cells.

Conclusion
These findings reveal an opposite influence of Rab4A on endosomal recycling of CD4 and CD38 that facilitates mTORC1 activation and thus causes pro-inflammatory T-cell lineage specification and triggers autoimmunity in SLE.
Nfkbid overexpression in NOD mice elicits complete type 1 diabetes resistance
Authors: Dwyer Jennifer R , Racine Jeremy J , Quinlan Anna , Presa Maximiliano , Chapman Harold D , Serreze David V 
Published: January 2023

Abstract
Type 1 diabetes (T1D) in both humans and the NOD mouse model is caused by the autoimmune mediated killing of pancreatic β-cells. Increased frequency or activity of autoreactive T cells and failures of regulatory T cells (Tregs) to control autoreactive T cells have both been implicated in T1D etiology. Due to the expression of MHC-I molecules on β-cells, autoreactive CD8+ T cells are likely the ultimate mediators of this destruction. Developing CD8+ T cells undergo selection processes in the thymus whereby most autoreactive clonotypes are eliminated during their development. Fine mapping of a genetic locus associated with defective thymic deletion of autoreactive CD8+ AI4 TCR transgenic (AI4) T cells in NOD mice led to the identification of Nfkbid, a NFκB signal modulator, as contributing to this phenotype. Ablation of Nfkbid in NOD mice by CRISPR/Cas9 results in a decreased frequency of autoreactive CD8+ AI4 T cells and an unexpected acceleration of T1D incidence, associated with reductions in the frequency and functional capacity of peripheral Tregs. Transgenic overexpression of Nfkbid in NOD mice paradoxically results in further decreased levels of circulating autoreactive CD8+ AI4 T cells. However, transgenic elevation of Nfkbid expression also increased the frequency and functional capacity of peripheral Tregs with a striking complete absence of T1D development in these mice. Studies are ongoing to define the mechanisms of T1D resistance mediated by transgenic overexpression of the transcriptional co-factor Nfkbid.
Resistant effect of sodium chloride on the development and function of TGF-β-induced CD4+ Foxp3+ regulatory T cells
Authors: Zheng Song Guo , Luo Yang , Wang Julie 
Published: January 2023

Abstract
High-salt diets inhibit the suppressive function of thymus-derived natural regulatory T cells (tTreg). TGF-β-induced ex vivo regulatory T cells (iTreg) represent another Treg subset that displays similarities and differences with tTreg. Here, we demonstrated that iTregs are completely stable and fully functional in the high salt condition. High salt did not affect the development, differentiation and function activities of iTreg in vitro and in vivo but affected the Foxp3 stability and function of tTreg in vitro and in vivo. In addition, high salt did not significantly change the transcription profiles of iTreg signature or pro-inflammatory genes. Therefore, we conclude that iTreg, unlike tTreg, is stable and functional in the presence of high salt. Thus, our findings provide another evidence that iTreg may have different biological features from tTreg and imply a greater potential to be employed in the clinical setting for patients with autoimmune diseases in the complicated role of environmental factors, including diet.
Adenosine:Adenosine Receptor (AR) Axis in Blood Brain Barrier (BBB) Permeability Regulation
Authors: Bynoe Margaret S 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a is a chronic, debilitating, neuroinflammatory disease that affects the central nervous system (CNS). MS affects about 2.5 million patients world-wide. MS patients experience a progressive loss in neurological function caused by immune-mediated axonal damage and demyelination in multiple areas of the brain and spinal cord. Despite years of research, the etiology of MS is still unknown. Studies using the dominant MS animal model, experimental autoimmune encephalomyelitis (EAE), demonstrate that myelin antigen-specific CD4 T cells can induce CNS inflammation, demyelination, and neurodegeneration, resulting in the loss of motor function (paralysis). Development of MS or EAE requires the entry of autoreactive immune cells into the CNS. Typically, the anatomical characteristics of the brain, such as the specialized endothelial cell tight and adherens junctions constitute the framework of the BBB, and limit the entry of lymphocytes into the CNS. We hypothesized that adenosine and/or adenosine receptors (ARs) expressed on BBB endothelial cells regulate the entry of immune cells and molecules into the brain. We showed that deletion of the adenosine-generating enzyme, CD73 (cd73−/−) expressed on BBB endothelial cells blocked immune cells entry into the brain. However, fulminant EAE could be induced in cd73(−/−) mice after the transfer of WT CD73(+)CD4(+) T cells, suggesting that CD73 must be expressed either on T cells or on BBB endothelial cells for disease induction. Next, we showed that blockade of the A2A AR block the entry of immune cells into the brain. Based on these findings we conclude that CD73 expression and adenosine receptor signaling are required for the efficient entry of lymphocytes into the CNS.
Overexpression of Pbx1-d, a novel splice isoform of Pbx1 associated with lupus susceptibility, regulates regulatory T cell plasticity
Authors: Choi Seung-Chul , Cornaby Caleb , Morel Laurence 
Published: January 2023

Abstract
Pbx1 controls chromatin accessibility to a large number of genes. The Pbx1-d dominant negative isoform lacking the DNA binding domain is more frequent in the CD4+ T cells from lupus patients than in healthy controls. Pbx1-d is associated with the production of autoreactive CD4+ T cells in mice carrying the Sle1a1 lupus susceptibility locus in the B6.NZM2410.Sle1.Sle2.Sle3 model. We have previously reported that Pbx1-d-Tg mice specifically expressing Pbx1-d in CD4+ T cells reproduced the phenotypes of Sle1a1 mice, and showed an impaired Foxp3+ regulatory T (Treg) cell homeostasis as well as increased inflammatory functions of their CD4+ T cells. To further study Treg cell homeostasis, we bred Pbx1-d-Tg mice with Foxp3-fate-mapping reporter constructs, and determined that Pbx1-d overexpression accelerated the loss of Foxp3 expression and the production of ex-Treg cells in unmanipulated mice. This result was confirmed by the homeostatic expansion of Fopx3-negative CD4+ T transferred into lymphopenic mice. RNAseq analyses showed that the increased ex-Treg production by Pbx1-d is associated with the expression of pro-inflammatory cytokines and an alteration of mitochondrial metabolism. Overall, these results suggest that Pbx1 regulate Foxp3 stability and that Pbx1-d promotes lupus development by decreasing the pool of effective Treg cells and promoting the production of the inflammatory ex-Treg cells.
Role of Jmjd6 in Aire expression and self-tolerance induction in the thymus
Authors: Matsubara Keisuke , Fukui Yoshinori 
Published: January 2023

Abstract

Introduction
To establish immunological self-tolerance in the thymus, medullary thymic epithelial cells (mTECs) express diverse sets of tissue-specific self-antigens (TSAs). This ectopic expression of TSAs largely depends on the transcriptional regulator Aire, yet the mechanism controlling Aire expression itself remains unknown. In this study, we aimed to examine the possible roleof Jmjd6, a lysyl hydroxylase for splicing regulatory proteins, in controlling Aire expression.

Material and methods
As conventional Jmjd6 KO mice die during perinatal period, 2DG-treated fetal thymi were prepared from the KO mice and control mice, and subjected to FACS analyses, immunohistochemical analyses and RNAseq analyses. The 2DG-treated fetal thymi were also grafted into C57BL/6 nude mice to examine its effect on self-tolerance induction in vivo. In addition, the conditional Jmjd6 KO mice (Foxn1-Cre Jmjd6lox/lox mice) were developed and crossed with a diabetes mouse model (OT1+RIP-mOVA+ mice) to analyze immunological tolerance under more physiological condition.

Results
Although Jmjd6 deficiency did not affect abundance of Aire transcript in mTECs, the intron 2 of Aire gene was not effectively spliced out in the absence of Jmjd6. As a result, the expression of mature Aire protein and TSAs were markedly reduced in Jmjd6-deficient mTECs, resulting in multi-organ autoimmunity when Jmjd6-deficient thymi were grafted into C57BL/6 nude mice. In addition, we found that TEC-specific deletion of Jmjd6 exacerbated development of autoimmune diabetes in a mouse model.

Conclusion
Jmjd6 controls Aire protein expression in mTECs for induction of self-tolerance in the thymus.
Phosphorylation of CBP by IKKα links intestinal homeostasis
Authors: Miaw Shi-Chuen , Lin Yi-Ting , Hsu Yu-Hua , Liu Chi , Chen Chieh-Chang , Shun Chia-Tung , Tu Chia-Hung , Yu Jhang-Sian , Wu Ming-Shiang , Chen Ching-Chow 
Published: January 2023

Abstract
CBP is a transcriptional coactivator participating in the regulation of DNA accessibility to transcription factors. Phosphorylation of human CBP by IKKα at serines 1382/1386 plays a critical role in regulating cell destiny via suppressing p53-mediated gene expression. We aimed to determine whether impaired phosphorylation of CBP is involved in the pathogenesis of disease. Hence, we designed and generated mutated serine 1383/1387 to alanine knockin mice (AA mice) to study whether they exhibit any phenotype alteration. AA mice showed an IBD-like phenotype with softer, looser and hemoccult stools and shorter colon length compared to the wild type mice. Increased p53 accompanied with apoptosis in colonic tissues of AA mice was demonstrated by IHC and TUNEL staining. In addition, male AA mice were more vulnerable to DSS-induced colitis with severe crypt loss and epithelial disruption. Elevated immune cells in mesenteric lymph nodes are also more prominent in AA mice with infiltration of neutrophil and macrophage. However, the differentiation of CD4+ T cells was not affected with Cbp mutation (AA) ex vivo. Colonic biopsies show that patients with ulcerative colitis have significantly lower phosphorylated CBP (Ser1382/1386) than healthy controls. Collectively, deficiency of NF-κB signaling in AA mice did not affect immune cells but modulated apoptosis of IECs. Our findings suggested that phosphorylation of CBP by IKKα might be a critical regulator to maintain intestinal homeostasis.
Inflammasome activation in macrophages is regulated by actin-bundling protein L-plastin
Authors: Joshi Hemant , Todd Betsy Elisabeth , Szasz Taylor , Anaya Edgar , Morley Sharon Celeste 
Published: January 2023

Abstract
Macrophage secretion of IL-1β is crucial to combat and clear bacterial infections. IL-1β release is tightly controlled by assembly of multimolecular inflammasomes (i.e. NLRP3, NLRC4, AIM2) and irregulated production can contribute to various pathologic conditions (i.e. acute respiratory disease and ventilator-associated lung injury). Prior research suggests that mechanical stress elevates macrophage IL-1β production. Because increased lung stiffness in diseases (e.g. acute respiratory distress syndrome) exerts mechanical stress on residing alveolar macrophages (AMs). Understanding how mechanical stress modulates AMs becomes crucial to elucidating the pathophysiology of pulmonary disease. We observed that IL-1β production in AMs was abrogated in absence of L-plastin (LPL), a hematopoietic restricted actin-bundling protein. LPL is also required for podosome formation. Podosomes are integrin-based, adhesive and mechanosensitive signaling organelles. LPL-deficient macrophages showed decreased IL-1β production when cultured on varying substrate stiffness. These observations suggest that LPL may link contact-based mechanosensation to inflammasome activation. Additionally, Pneumolysin toxin in Streptococcus pneumoniae infection activates NLRP3 and may exacerbate inflammatory pathogenesis in stiffened lungs. Further, we will investigate LPL mediated mechano-sensitive inflammasome activation in pneumococcal lung infections using mouse models. Our observations indicate previously unknown mechanosensitive pathway for inflammasome activation in macrophages. Understanding the molecular mechanism will aid in developing immunomodulatory therapies to treat inflammatory disorders and diseases.
Targeted expansion of tissue-resident CD8+ T cells to boost cellular immunity in the skin
Authors: Hobbs Samuel J , Nolz Jeffrey C 
Published: January 2023

Abstract
Tissue-resident memory (TRM) CD8+ T cells are positioned within environmental barrier tissues to provide a first-line of defense against pathogen entry. Whether these specialized T cell populations can be readily boosted to enhance tissue-specific protective immunity has not been thoroughly investigated. Here, we show that cutaneous immunization with Vaccinia virus establishes rare, but highly functional antigen-specific TRM CD8+ T cells from the endogenous T cell repertoire. Repeated activation of endogenous TRM CD8+ T cells using only topical application of antigenic peptide caused delayed-type hypersensitivity (DTH) and expanded the antigen-specific TRM CD8+ T cell population in the challenged skin by ~15-fold, resulting in significantly increased anti-viral protective immunity. Rather than the result of local proliferation, expansion of TRM CD8+ T cells required circulating memory T cells to be recruited into the skin to become tissue-residents. Although circulating memory CD8+ T cells of other antigen-specificities trafficked into the skin during TRM-mediated DTH, they failed to differentiate into CD69+ TRM cells. However, circulating memory CD8+ T cells of a different antigen-specificity could be coerced to become tissue-resident using a dual peptide challenge strategy, where one peptide causes TRM-mediated DTH and the second peptide ‘captures’ only the desired antigen-specific memory CD8+ T cells in the skin. Overall, our study demonstrates that established TRM CD8+ T cells can be rapidly expanded to enhance tissue-specific cellular immunity, but also reveals how pathogenic T cells specific for commensal or environmental antigens could continually accumulate in the skin following repeated exposures.