bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein phosphatase 2A promotes IL-2R signaling in human regulatory T cells
Authors: Ding Ying , Yu Aixin , Malek Thomas R. 
Published: January 2023

Abstract
Low-dose IL-2 therapy is a direct approach to boost Tregs and promote immune tolerance in autoimmune patients. The selective response of Tregs to low-dose IL-2 has been suggested to be due to high level of CD25 and activity of the Ser/Thr phosphatase, PP2A. Here we directly assessed the contribution of these two parameters in promoting IL-2 signaling in human Tregs. IL-2-induced tyrosine phosphorylation of STAT5 (pSTAT5) was proportional to CD25 levels on human CD4+ T cells, directly demonstrating that high IL-2R levels promote the Treg response to low-dose IL-2. To evaluate the role of PP2A, expanded human Tregs were transduced with lentivirus to overexpress or knock down the PP2A catalytic subunit (PP2Ac). Overexpression of PP2Ac increased the level of all IL-2R subunits and promoted phosphorylation of Jak3 at Tyr980/981. Compared to control-transduced cells, PP2Ac-overexpressed Tregs were 3-fold more sensitive to IL-2 based on pSTAT5 activation. Increased expression of CD25 only partially accounted for this enhanced activation of pSTAT5. Consistent with these findings, knockdown of PP2Ac in Tregs significantly reduced the pSTAT5 responses to IL-2. Overexpression of PP2Ac in Tregs also increased the expressions of proteins related to growth, survival, activation, and immunosuppressive function, and included several IL-2-regulated genes. Collectively, these findings indicate that PP2A promotes IL-2R signaling through multiple mechanisms, one related to control of IL-2R expression and another that may directly regulate IL-2R signaling.
PLGA-microsphere delivery of insulin and IGRP epitopes as a therapy for type 1 diabetes
Authors: Racine Jeremy J. , Leeth Caroline M. , Serreze David V. 
Published: January 2023

Abstract
Autoreactive CD8+ T-cells are the ultimate effectors destroying pancreatic β–cells during type 1 diabetes (T1D), revealing a critical role for HLA class I molecules in disease pathogenesis. The HHD transgene contains the α1 and α2 domains of the T1D susceptible variant HLA-A*02:01, covalently linked to human β2m with the α3, transmembrane, and cytoplasmic domains being of murine H2-Db origin. Introduction of HLA-A2.1 into NOD mice via the HHD transgene restores T1D development to NOD.β2m−/− mice. Using these NOD.β2m−/−-A2 mice, we previously identified four epitopes (INS1/2A2–10, INS1B5–14, IGRP265–273 and IGRP228–236) that are targets of CD8+ T-cells in both NOD mice and humans. When coupled to a clinically relevant delivery-mechanism, poly(lactic-co-glycolic acid) microspheres, delivery of these peptides during both early and late-prodromal stages of T1D can ameliorate progression to overt diabetes in NOD.β2m−/−-A2 mice. Delivery of all four peptides was capable of ameliorating T1D and insulitis when delivered every three weeks whether the injections were continued throughout the study (started at six or ten weeks of age) or whether the injections were only given three times (starting at ten weeks of age). After three injections of all four peptides, CD8+ T-cell recall responses to IGRP265–273 and IGRP228–236 were reduced. Attenuation of CD8+ T-cell responses correlated with a reduction in PD-1+ effector CD8+ T-cells as well as a small increase in PD1− CXCR3− central memory CD8+ T-cells in the popliteal LN after footpad priming. Work is ongoing to determine the effectiveness and dosing in 2nd generation HLA- “humanized” NOD-cMHCI−/−-A2 mice that retain murine FcRn functionality.
Tailoring a new generation of chimeric antigen receptors for regulatory T cells
Authors: Ferreira Leonardo , Kaul Anupurna , Guerrero-Moreno Ryan , Fontenot Jason D. , Bluestone Jeffrey A. , Tang Qizhi 
Published: January 2023

Abstract
Chimeric antigen receptors (CARs) direct T cells to target antigens with an extracellular antigen-binding domain and simultaneously deliver TCR signaling and costimulation, resulting in potent antigen-specific T cell activation. This technology has revolutionized our capacity to create tumor-specific effector T (Teff) cells. CAR-Treg engineering is a promising strategy to create antigen-specific Tregs for treating autoimmune and inflammatory diseases. Yet, there are stark differences in signaling between Tregs and Teff cells. Here, we interrogated CAR-mediated signaling in human Tregs and Teff cells using twenty-four CARs with distinct signaling architectures, including CD28 mutants, TNFR family members, and inhibitory receptors. CD28 signaling plays a key role in Treg development and function. Accordingly, CAR-mediated CD28 signaling was indispensable for robust CAR Treg expansion, requiring intact PI3K, ITK, and LCK binding. Similar dependence on CD28 signaling was observed in Teff cells. Treg maturation has been shown to be accompanied by the upregulation of TNFR family members. CARs incorporating TNFR signaling generally resulted in delayed activation kinetics in both Tregs and Teff cells. Strikingly, however, CAR-mediated CD30 signaling led to constitutive activation in Tregs in the absence of antigen, whereas in Teff cells it resulted in delayed activation. Inhibitory receptor expression, a hallmark of Tregs, triggers Teff cell exhaustion. CAR-mediated inhibitory receptor signaling, except for PD1, specifically hampered activation of Teff cells. Altogether, our results indicate that CAR engineering can uncover differences in signaling between human Tregs and Teff cells and maximize CAR-Treg therapies.
Development of citrullinated-vimentin-specific CAR for targeting Tregs to treat autoimmune rheumatoid arthritis
Authors: Raffin Caroline , Zhou Yu , Piccoli Luca , Lanzavecchia Antonio , Sadelain Michel , Tareen Semih U. , Fontenot Jason D. , Bluestone Jeffrey A. 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is one of the most common chronic autoimmune diseases that is characterized by an aberrant inflammation of the synovial membrane that causes irreversible joint and bone damage. Regulatory T cells (Tregs) are defective in RA patients while adoptive transfer of expanded autologous Tregs efficiently reversed disease in collagen-induced arthritis (CIA), an animal model of RA. These studies strongly suggest that Treg therapy may be effective in the treatment of RA patients by reducing joint inflammation and inducing immune tolerance. However, clinical treatment with polyclonal Tregs may lead to general immunosuppression. Thus, the development of precise RA Ag-specific Tregs would increase specific activity, promote selective migration to the site of the abnormal inflammation and enhance their function. Thus, we engineered chimeric antigen receptor (CAR)-expressing Tregs specifically targeting an antigen present in the joint of RA patients to induce a localized and effective immunosuppressive response. We developed a single chain Fv directed against a posttranslational modified intermediate filament protein, citrullinated vimentin (CV), an antigen found, almost exclusively, in the extracellular matrix of the synovial tissue of the RA patients and implicated in the pathogenesis of the disease. The scFv was grafted into a functional CAR construct, transduced into human Tregs and shown to react with CV expressed in RA patient synovial fluid and CV-expressing cells. Studies are underway to demonstrate the functional activity of these CAR-expressing Tregs in in vivo mouse models a validation step in the development of a promising therapeutic tool to treat RA and potentially other autoimmune disorders.
IL36-Mediated Skin Inflammation Requires Signaling Through Chemokine Receptor CCR6.
Authors: Campbell James J. , Ebsworth Karen , Ertl Linda S. , McMahon Jeffrey P. , Yau Simon , Wang Yu , Liu Shirley , Dang Ton , Zhang Penglie , Schall Thomas J. , Singh Rajinder 
Published: January 2023

Abstract
Generalized pustular psoriasis (GPP) is a rare inflammatory skin disorder with an etiology distinct from common plaque psoriasis. GPP patients often do not respond to therapeutic agents used routinely to treat plaque psoriasis. Genetic evidence suggests that GPP arises from dysfunction in the IL36/IL36Ra/IL36R signaling axis, and many aspects of GPP can be re-created in the mouse by intradermal (ID) injection of pre-activated IL36. We have used this ID-IL36 model to study the leukocyte populations that accumulate within GPP skin. In a previous study, we reported that a small molecule CCR6 antagonist, CCX2553, ameliorates inflammation in an imiquimod-induced model of plaque psoriasis, and we now find this is to be the case in the GPP model as well. However, in contrast to the imiquimod model, a conventional CD4+ αβ T cell population accumulates in the ID-IL36-treated skin instead of the characteristic γδT17 population found in imiquimod-treated skin. CCX2553 reduces IL36-induced inflammation while preventing skin accumulation of this CD4+ αβT cell population. Thus, although disparate T cell populations are associated with each model, inflammation is ameliorated by CCR6 antagonism in both models. These findings suggest that CCR6 may constitute a novel target for a mechanistically distinct approach towards GPP therapy.
Deletion of adenosine A2A receptor blocks the beneficial effects of Lactobacillus reuteri on Treg-deficiency-induced autoimmunity
Authors: Liu Yuying , He Baokun , Hoang Thomas K. , Tran Dat Q. , Rhoads J Marc 
Published: January 2023

Abstract
The lack of Foxp3+ regulatory T cells (Tregs) causes a lethal, CD4+T cell-driven autoimmune disease in scurfy (SF) mice and humans characterized by immunodysregulation, polyendocrinopathy, enteropathy, with X-linked inheritance (or IPEX syndrome). We observed that adenosine 2A receptor (A2A) activation limits inflammation and tissue damage, and that Lactobacillus reuteri DSM 17938 (LR) modulates the abnormal fecal microbial community associated with the disease, stimulating the production of bioactive metabolites, especially inosine by activating A2A expressed on T cells. To conclusively provide evidence of a central role of A2A in the actions of LR, we generated A2A null SF mice (SF·A2A−/−). Male mice were given daily by gavage culture media (MRS) or LR in MRS (107CFU/day), starting at d8 to d22 for plasma and tissue analysis or long-term survival We found that A2A receptor deletion in SF mice did not affect early life events, the development of a lymphoproliferative disorder, or hyper-production of proinflammatory cytokines. LR treatment prolonged survival and reduced multi-organ inflammation in SF mice. In marked contrast, A2A receptor deletion reversed the effect of LR in prolonging lifespan in SF mice and negated the effects of LR on inflammation in the liver and lungs of SF mice. A2A deletion also inhibited LR-mediated reduction of TH1/TH2 cells and reversed the effect of LR on plasma pro-inflammatory cytokines. In conclusion, (a) the absence of the A2A receptor does not affect the development of disease in SF mice, and (b) the A2A receptor plays a critical role in immunomodulation produced by LR treatment. Lactobacillus reuteri and A2A receptor activation may have a role in other Treg dysfunction-mediated autoimmune diseases.
Nanoparticles Containing an Insulin-ChgA Hybrid Peptide Prevent Transfer of Type 1 Diabetes in NOD Mice by Expanding Foxp3+ Tregs
Authors: Jamison Braxton , Neef Tobias , Miller Stephen D. , Haskins Kathryn 
Published: January 2023

Abstract
In Type 1 Diabetes (T1D) autoreactive T cells destroy insulin-producing β-cells in the pancreatic islets. A major focus of our lab has been to identify novel peptide ligands for diabetogenic CD4 T cells isolated from non-obese diabetic (NOD) mice. We have identified a novel post-translational modification whereby a peptide from chromogranin A is covalently bound to a fragment from proinsulin, resulting in formation of a hybrid insulin peptide (2.5HIP) that is a potent ligand for the CD4 T cell clone BDC-2.5. Using an MHC class II tetramer to track the frequency and phenotype of endogenous 2.5HIP-reactive T cells in NOD mice, we found that these cells play a critical role in the disease process. The purpose of this project was to determine if poly(lactide-co-glycolide) (PLG) nanoparticles (NPs) loaded with 2.5HIP could be used to prevent induction of diabetes by transfer of BDC-2.5 TCR transgenic T cells cells into NOD.scid mice. We have found that i.v. infusion of 2.5HIP-coupled NPs (2.5HIP-PLG) one day after T cell transfer can almost completely prevent diabetes. Treatment with 2.5HIP-PLG leads to reduced T cell trafficking to the pancreas early on, as well as in vivo expansion of long-lived Foxp3+ regulatory T cells (Tregs) that express inhibitory receptors, membrane bound TGFβ-1/LAP, and stability markers. We predict that stable long-lived Tregs are critical for suppressing pathogenic IFN-γ producing T cells and maintaining long-term tolerance in this system. The end goal of this study is to determine if NPs containing HIPs can be used to prevent and/or reverse spontaneous disease in NOD mice. Results from these studies could have significant implications for the development of an antigen-specific therapy for T1D patients.
Extending remission and reversing new onset type 1 diabetes by targeted ablation of autoreactive T cells
Authors: Carroll Kaitlin , Elfers Eileen , Stevens Joseph , McNally Jonathan P. , Hildeman David , Jordan Michael Brian , Katz Jonathan D. 
Published: January 2023

Abstract
Preserving endogenous insulin production is clinically advantageous and remains a vital unmet challenge in the treatment and reversal of type 1 diabetes (T1D). While broad immunosuppression has had limited success in prolonging the so-called remission period, it comes at the cost of compromising beneficial immunity. Here, we employed an alternate strategy to specifically deplete the activated diabetogenic T cells that drive pathogenesis while preserving not only endogenous insulin production but also protective immunity. Effector T cells, such as diabetogenic T cells, are naturally poised on the edge of apoptosis because of activation-induced DNA damage that stresses the p53 regulation of cell cycle. We have found that the combined use of small molecular inhibitors that further potentiates p53 while inhibiting G2/M cell cycle checkpoint control drives apoptosis of activated T cells in vivo. When delivered at the onset of T1D these inhibitors eliminate diabetogenic effector T cells, prolong remission, preserve functional islets, and protect islet allografts while leaving naïve, memory, and regulatory T cell populations functionally untouched. Thus, the targeted manipulation of p53 and cell cycle checkpoints represents a new therapeutic modality for the preservation of islet beta cells in new onset type 1 diabetes or after islet transplant.
ALLERGIC LUNG INFLAMMATION IN OFFSPRING OF PREGNANT MICE EXPOSED TO ORGANIC DUST
Authors: Nascimento Amanda AN , Schneberger David , Kirychuk Shelley , Pandher Upkar , Thompson Brooke , Singh Baljit 
Published: January 2023

Abstract
The hygiene hypothesis shows that there is a strong correlation between microbial exposures in early life and the absence of allergies and asthma. However, studies also show that these same microbial exposures in early life can cause psychiatric and behavioral problems. Lipopolysaccharide (LPS), originating from microbes, is ubiquitous in animal holding facilities such as pig barns. The influence of CD34, an adhesion protein important in development of lung inflammation, in the association between microbial exposures and asthma, are not known, nor is the association between CD34 and behavior. We studied pulmonary immune responses and behavior of male and female offspring of wild-type and CD34−/− pregnant mice exposed to pig barn air for 4 hours/day for 5 days/week for 21 period of pregnancy. The ovalbumin protocol was used to induce asthmatic responses in the offspring. All OVA-treated CD34−/− and WT mice had more AhR, leukocytes and IL-4, IL-5, IL-6, and IL-13 compared to their respective controls (P&lt;0.05) showing development of asthmatic response. All CD34−/− asthmatic as a group had lower AhR, total leukocytes and levels of IL-4, IL-5, IL-6, and IL-13 compared to WT asthmatic mice. However, CD34−/− and WT asthmatic females compared to CD34−/− and WT males asthmatic mice had higher AhR, total leukocytes and cytokine levels. Also, in the general activity in open field the asthmatic females had lower locomotion (P &lt; 0.05) compared to the male asthmatic mice These data show that female offspring of those exposed to LPS-contaminated environment had higher degree of asthmatic lung responses and behavioral changes compared to the males affect females more frequently than males
FLX193: A Potent, Selective CCR4 Antagonist for Allergic Disorders
Authors: Jorapur Aparna , Marshall Lisa , Bradford Delia , Brovarney Martin , Chian David , Wadsworth Angela , Sanchez Jerick , Jacobson Scott , Karbarz Emily , Robles Omar , Younai Ashkaan , Ketcham John , Ng Andrew , Tivitmahaisoon Parcharee , Pookot Deepa , Marubayashi Sachie , Kozon Nathan , Colas Christophe , Okal Abood , Cutler Gene , Wustrow David , Schwarz Jacob , Talay Oezcan , Brockstedt Dirk , Wong Brian 
Published: January 2023

Abstract
Type 2 helper T cells (Th2)cells have been shown to express CCR4 receptor, and play a critical role in driving the pathogenesis of asthma and atopic dermatitis. FLX193 is a best-in-class, highly-potent and selective small molecule CCR4 antagonist under investigation for the treatment of allergic disorders. FLX193 blocked migration of CCR4+ Th2 cells (human and mouse) towards CCL17 and CCL22 in an in vitro chemotaxis assay. FLX193 is well-tolerated in animals at efficacious doses. In an Ovalbumin (OVA)-induced asthma model, FLX193 significantly reduced lymphocyte and eosinophil counts in the Bronchoalveolar lavage (BAL) fluid and showed a reduction of the effector Th2-relevant cytokines IL-5 and IL-13. FLX193 treatment also reduced the levels of CCL17 and CCL22 in the BAL fluid, indicating an overall reduction of inflammation. In addition, we used an atopic dermatitis mouse model to demonstrate that treatment with FLX193 decreased CCR4+ T-cell mediated inflammation. Hence, FLX193 shows promise in the treatment of atopic dermatitis.
Anti-CD4 autoantibody-mediated failure of CD4+ T cell reconstitution in HIV-infected patients under viral-suppressive ART
Authors: Jiang Wei , Luo Zhenwu 
Published: January 2023

Abstract
Increased mortality and morbidity occur in HIV-infected patients who fail to increase CD4+ T cell counts under viral-suppressive antiretroviral therapy (ART). Here we identified an underlying mechanism. Plasma anti-CD4 IgGs were measured by ELISA in 17 healthy controls, 26 HIV+ immunologic responders (IR, aviremic, CD4+ T cell counts ≥ 500 cells/μL), and 22 non-responders (NR, aviremic, CD4+ T cell counts &lt; 350 cells/μL). Anti-CD4 IgGs were purified from plasma of 21 NR by affinity purification. Antibody-dependent cytotoxicity (ADCC) was performed in CD4+ T cells co-cultured with NK cells in presence of anti-CD4 IgGs or control IgGs in vitro. Plasma microbiome was analyzed by bacterial 16S DNA sequencing. Elevated plasma levels of anti-CD4 IgGs were found in NR [median (interquartile range, ng/mL), 92 (53–166)] compared to IR [26 (16–82)] and healthy controls [16 ng/mL (9–24)] (P &lt; 0.001 between NR and two controls, ANOVA). Higher plasma level of anti-CD4 IgG correlated with blunted CD4+ T cell recovery (r = −0.53, P = 0.0002, Spearman correlation test). Furthermore, purified anti-CD4 IgGs induced NK cell-dependent CD4+ T cell cytolysis (P = 0.02). Notably, Simpson diversity was lower in patients with plasma anti-CD4 IgG ≥ 50 ng/mL compared to patients with anti-CD4 IgG &lt; 50 ng/mL (P = 0.04). There was an inverse correlation between plasma anti-CD4 IgG and the Simpson diversity index in patients (r = −0.47, P = 0.03) but not in healthy controls. These results indicate a possible link between microbiome and B cell dysfunction in HIV, and anti-CD4 IgGs may play an important role in preventing CD4+ T cell reconstitution despite viral-suppressive ART.
PET imaging of TSPO in a rat model of sepsis induced by peritoneal polymicrobial infection
Authors: Barichello Tatiana , Giridharan Vijayasree V , Petronilho Fabricia , Generoso Jaqueline S , Dominguini Diogo , Dal-Pizzol Felipe 
Published: January 2023

Abstract

Background
Sepsis is a life-threatening acute organ dysfunction secondary to infection that affects more than 30 million people worldwide. In the USA, 1.5 million people develop sepsis, and at least 250,000 Americans die from sepsis each year. After hospitalization, patients suffer from long-term impairments in memory, attention, verbal fluency, and executive functioning. The translocator protein (TSPO), marker of activated microglia astrocytes cells, can be measured in vivo using positron emission tomography (PET). Our working hypothesis is that systemic inflammation associated with sepsis activate microglia cells, which will later lead to further long-term cognitive impairment in sepsis survivors.

Methods
To test this hypothesis, adult male Wistar rats were subjected to a gold standard sepsis model induced by cecal ligation and perforation (CLP) surgery to induce peritoneal poly microbial sepsis or sham surgery as a control group. At 24 hour after the surgery the animals were subjected to translocator protein (TSPO) microPET imaging with [11C]PBR28. Following the imaging, TSPO, cytochrome C, cytokines/chemokines, microglia (Iba-1) and astrocyte marker (GFAP) were measured in the prefrontal cortex and hippocampus of the septic animals.

Results
septic animals presented and increased uptake of [11C]PBR28-microglia activation in the whole brain compared to control at 24 after the CLP surgery. The expression of IL-1α, IL-1β, IL-6, IL-18, TNF-α, IFN-γ and Iba-1 increased in the hippocampus of septic rat.

Conclusion
The upregulation of TSPO expression in the hippocampus of septic rat brain is a possible mechanism associated with long-term cognitive impairment in sepsis survivors.
High T cell percentage predicts improved overall survival in de novo Acute Myeloid Leukemia
Authors: Saultz Jennifer N , Wang Weiwei , Lind Evan F , Kaempf Andy , Fan Guang , Mori Tomi , Park Byung 
Published: January 2023

Abstract

Intro
Acute myeloid leukemia (AML) is associated with defects in innate and adaptive immunity leading to immune evasion and leukemia survival. Given the important connection between the immune system and AML, our group sought to understand the prognostic significance of immune subsets in the bone marrow.

Methods
Patient samples were obtained from the Oregon Health and Science University (OHSU) pathology department between September 2010 and March 2016. This cohort study includes 82 newly diagnosed adult AML patients who had a bone marrow biopsy that was subjected to flow cytometry and a targeted-NGS panel.

Results
This retrospective cohort of 82 newly diagnosed AML patients was 53.7% male with a median age of 61 years (range 18 – 83). Using 2017 ELN risk guidelines, 40% of patients were classified as favorable, 24% as intermediate, and 35% as adverse. The percent T cells of lymphocytes ranged from 41.0 to 90.9 (median 72.5). The percent of NK cells ranged from 2.1 to 22.6 (median 8.7). Separate Cox regression models were applied to each immune cell group in both the univariable and multivariable settings, with the latter models accounting for patient age and ELN risk. Higher T cell percentages were correlated with longer survival, even when adjusting for age and ELN risk (p=0.024; HR=0.87 [95% CI: 0.78 – 0.98] for each 5-unit increase). Conversely, in the absence of other patient features, higher NK cell percentages were predictive of worse OS (p=0.015).

Conclusions
In this study, we show that higher T cell percentages at diagnosis are associated with improved OS. This association is most evident in patients at least 60 years old or those with intermediate ELN risk.