bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4 T cell expression of PTIP is necessary for epigenetic maintenance of Th1/Th17 responses during Cryptococcus neoformans infection
Authors: Eastman Alison J , Gupta Kanav , Neal Lori , Xu Jintao , Zhou Guolei , Malachowski Antoni , Dressler Gregory R. , Kunkel Steven L , Schaller Matthew , Olszewski Michal A 
Published: January 2023

Abstract
Containment and clearance of opportunistic fungal pathogen Cryptococcus neoformans (CN) requires Th1/Th17 polarized CD4 T cells. Studies show that Th1/Th17 T-cell polarization is linked to enriched chromatin activation at histone 3 lysine 4 (H3K4). DNA repair enzyme PTIP forms a complex with MLL3/4 H3K4 methyl transferases, but its role in regulation of immune-related genes remains unknown. We hypothesized that the absence of PTIP in CD4 T cells would result in a defect in generation and/or maintenance of Th1/Th17 driven immune protection against CN infection. CD4Cre+, PTIP knockout mice (CD4-PTIP-KO) and their control Cre- littermates were infected with CN and their fungal burden and T cell polarization assessed at 3 and 6 weeks post-infection (wpi). There were few statistically significant differences at 3 wpi, but no defects in IFNγ and TNFαproduction in these mice. However, by 6 wpi we observed profound defects in fungal clearance and the expression of hallmarks of Th1 and Th17 responses. CD4-PTIP-KO mice had diminished fungal clearance by 1.5-log and showed diminished frequency of IFNγ, TNFα, and IL-17 producing CD4 T-cells as well as suppressed global production of these cytokines. Furthermore, frequency of IFNγ-IL-17 dual-producing CD4 T cells, previously found to correlate with clearance, was diminished in CD4-PTIP-KO mice. Interestingly no T-cell activation defect (frequency of CD44hi and CD62L low) was altered in CD4-PTIP-KO mice. Collectively, we conclude that PTIP is not necessary for induction of Th1 and Th17 polarized T cells but it is crucial for maintaining robust Th1/Th17 cytokine production by polarized T cells throughout C.neo infection, presumably via epigenetic stabilization of CD4 T cells Th1/Th17 programing.
Necrotic liver induces pyroptosis through Caspase-1 in eosinophils
Authors: Macapagal Daphne , Connor Jane , Ramalingam Thirumalai R , Wynn Thomas A , Mustelin Tomas Mikael , Davidson Todd S 
Published: January 2023

Abstract
During sterile inflammatory reactions damage associated molecular patterns (DAMPS) are released from necrotic cells and recruit immune cells to the sites of tissue injury. We found that necrotic liver homogenates, when injected intraperitoneally, can recruit large numbers of immune cells. Among these immune cells were activated eosinophils. Eosinophils are polymorphonuclear leukocytes typically found within tissues of the gastrointestinal and respiratory tracts. While eosinophils are well known to accumulate in the lungs of asthmatics or in response to helminths and parasites, several studies have shown the presence of eosinophils in liver biopsies of drug-induced liver injury, chronic hepatitis C and liver fibrosis. The prevalence of eosinophilic infiltrates in the liver points to a correlation between infiltration and disease outcome. Our results demonstrated eosinophil activation upon exposure to necrotic liver components. Exposure to necrotic liver cells induced eosinophil degranulation as measured by expression of CD107a and eosinophil peroxidase release as measured by ELISA. Further study of eosinophil activation during necrotic liver exposure showed IL-1β and IL-18 release as well as cell death. All of these responses were dependent upon caspase-1 activation. Caspase-1 mediated cell death accompanied by IL-1β and IL-18 release are hallmarks of pyroptosis, an inflammatory cell death pathway. We verified eosinophil pyroptosis in vivo using a liver fibrosis model involving Schistosoma mansoni infected mice. Eosinophils extracted from S. mansoni infected livers showed caspase-1 activation and cytokine release indicating that these cells undergo pyroptosis in vivo in response to hepatocyte injury.
A Novel Role for the 4E-BP/eIF4E Axis in B Cell Antibody Class Switching
Authors: Chiu Honyin , So Lomon , Fruman David A 
Published: January 2023

Abstract
During an immune response, activated B cells give rise to antibody secreting plasma cells to fight infection. B cells undergo a process known as antibody class switch recombination (CSR) to produce different classes of antibodies with varying effector functions. The mammalian target of Rapamycin (mTOR) signaling pathway is activated during this process and inhibition of mTOR suppresses both proliferation and differentiation into antibody secreting cells. mTOR is a kinase that is found in two distinct complexes, mTORC1 and mTORC2 and B cells deficient in mTOR have impaired survival, proliferation and differentiation. It has been shown that antibody class switch recombination requires B cell division, however it is unclear if there is another regulatory mechanism through mTOR that is independent of proliferation. The mTORC1 inhibitor rapamycin, at either low concentrations or when added after a B cell has committed to divide, suppresses class switching while preserving proliferation. Mechanistic investigation of the mTORC1 substrate 4E-BP, an inhibitor of eIF4E and cap-dependent translation, showed that blocking the 4E-BP/eIF4E axis can decrease antibody class switching independently of proliferation. Genetic deletion of 4E-BP1 and 4E-BP2 isoforms partially rescues from the effects of rapamycin on class switching to IgG1. These results uncover a novel role for mTORC1 and the 4E-BP/eIF4E axis in B cell antibody class switching, suggesting that cap-dependent translation regulates key steps in B cell differentiation. Further study of this pathway may provide mechanistic insight into antibody-mediated autoimmune diseases such as lupus and arthritis.
Dynamic imaging of a Tbet-Foxp3 double reporter in the course of Th1 mediated immune response
Authors: Akkaya Billur , Holstein Amanda H , Kamenyeva Olena , Akkaya Munir , Shevach Ethan M 
Published: January 2023

Abstract
T cells can integrate various environmental cues and acquire different transcription profiles through the differentiation processes. The transcription factor T-bet is switched on by CD4+ T cells during type 1 inflammation and acts as the master regulator of Th1 lineage of T cell differentiation and function. Strong Th1 responses are usually elicited by intracellular pathogens and must be counterbalanced by Foxp3+ Treg cells to prevent immunopathology. Recently, it was demonstrated that T-bet-deficient Treg cells fail to rescue Foxp3-deficient mice from Th1 cell-mediated inflammatory disease raising the questions how and why Tregs adapt the unique Th1 type transcription profile. Using a TbetZsGreen-Foxp3-RFP double reporter mouse model, we have addressed those questions by confocal microscopy of the live tissue sections, intravital microscopy of the popliteal lymph node and flow cytometry. We have demonstrated that Tregs in the T cell areas of the lymph node co-localized with Tbet expressing cells forming large clusters especially at the T cell-B cell border. B cell area also contained T-bet expressing cells both at the steady state and during type 1 inflammation, which were more sparse and moved remarkably faster compared to the T-bet expressing cells in the T cell area. Altogether, this suggests that Tregs are localized in close proximity to T-bet expressing cells in the live lymph nodes and may modulate their movement characteristics. The functional relevance of this needs to be further explored.
NR4A3 controls CD8+ T cell metabolism and differentiation
Authors: Odagiu Livia , Boulet Salix , Daudelin Jean-François , Labrecque Nathalie 
Published: January 2023

Abstract
Following an infection, naive CD8+ T cells expand and differentiate into two major populations of effectors: short-lived effector cells meant to die by apoptosis and memory precursor effector cells (MPECs) destined to survive as memory cells that will confer long-term protection. We postulated that the transcription factor NR4A3, a member of the orphan nuclear receptor family, whose expression is induced by TCR signalling, will regulate in vivo CD8+ T cell response. To elucidate the role of NR4A3 during CD8+ T cell response, we have adoptively transferred wild-type and Nr4a3−/− OT-I T cells (specific for the ovalbumin (OVA) peptide in the context of Kb) into naive recipients and analyzed their response following infection with a recombinant strain of Listeria monocytogenes encoding OVA. Although Nr4a3+/+ and Nr4a3−/− OT-I T cells expanded similarly, we observed an increased generation of MPECs at the peak of the T cell response, which led to an enhanced (2–3X) generation of memory T cells. Furthermore, Nr4a3−/− effector and memory T cells produce more cytokines than their wild-type counterpart. The analysis of the early T cell response demonstrated that NR4A3 controls the metabolic activity of activated T cells, as Nr4a3−/− OT-I T cells express less nutrient receptors and have reduced phosphorylation of S6. Altogether, these results suggest that NR4A3 controls effector and memory T cell differentiation by modulating their metabolic activity during the immune response.
Early window of susceptibility of allospecific CD4+ T cells to AhR-induced suppression reflects excess production of IL-2, over-expression of regulatory genes and repression of cell cycle genes.
Authors: Kerkvliet Nancy , Ehrlich Allison , Pennington Jamie , Wang Xisheng , O’Donnell Edmond , Tilton Susan , Rohlman Diana , Funatake Castle J 
Published: January 2023

Abstract
Activation of AhR in CD4+ T cells leads to suppression of Th1-, Th2- and Th17-mediated immune responses. In allograft models, the first 3 days of the immune response represent a critical window for AhR activation during which significant changes in donor CD4+ T cells occur. However, little is known about the mechanisms that underlie this early window of CD4+ T cell sensitivity to AhR activation and whether limiting AhR signaling to this early window is sufficient to suppress the allograft response. We used a rapidly metabolized AhR ligand, 10-Cl-BBQ, to show that early AhR activation alone is indeed sufficient to suppress GVHD. Early activation of AhR was also sufficient to increase the frequency of CD4+ Foxp3+ T cells on day 15 of the GVH response. AhR activation induced an early increase in IL-2 production by donor CD4+ T cells that was responsible for the Tr1-like phenotype on day 2 and the Foxp3+ Treg phenotype on day 15. However, blockade of IL-2 signaling, which prevented the induction of Foxp3+ Tregs, failed to alter AhR-induced suppression of GVHD. Global gene expression analysis of purified alloresponding donor CD4+ T cells on day 2 and 3 of the GVH response revealed up-regulation of many genes associated with regulatory T cells and down-regulation of genes involved in cell cycle progression. Reduced cell cycling was validated by reduced BrdU incorporation on day 4 of the GVH response. These results are consistent with a model of AhR signaling during naïve CD4+ T cell activation leading to induction of unique AhR-Tregs that induce premature cell-cycle arrest in effector CD4+ T cells; the lack of mature CD4+ T helper cells prevents the maturation and differentiation of allospecific CD8+ CTL leading to suppression of GVHD.
Identification of BATF target genes critical to its function in immune responses
Authors: Morman Rosemary E , Poston Stacie , Taparowsky Elizabeth J. 
Published: January 2023

Abstract
BATF, an immune specific AP-1 transcription factor, functions together with IRF4 and JUNB to regulate genes important for antibody class switch recombination (CSR) in B cells and for the functional differentiation of distinct CD4+ T helper (Th) subsets, including Th2, Th9, Th17 and Tfh cells. BatfΔZ/ΔZ(KO) mice display phenotypes directly related to deficiencies in the cell types mentioned above. In an attempt to define the gene expression changes responsible for these phenotypes, RNA-seq was performed to profile transcripts in KO versus WT mouse B cells. Bioinformatic analyses identified 47 genes whose transcripts were either over-represented or under-represented in the absence of BATF. Many of the transcripts found to be misregulated in KO B cells were misregulated in KO T cells as well, suggesting that these genes are common molecular targets of BATF transcriptional activity. Retroviral mediated re-expression of BATF in the KO cells resulted in the proper regulation of these target genes. Furthermore, BATF reconstituted KO B cells were able to undergo CSR and naive CD4+ T cells re-expressing BATF could be differentiated into Th2 and Th17 subsets. Our current efforts are employing this rescue strategy with retroviruses expressing BATF proteins modified for their DNA binding, dimerization and transcriptional properties to better understand the molecular parameters that control how BATF regulates gene sets in B cells and T cells. Our long term goal is to exploit the regulation of BATF for in vivo strategies to manage inflammation and autoimmune disorders.
MDM2 ubiquitin ligase in Lupus CD4 T-Cell pathology.
Authors: Titov Anton A , Brusko Todd M. , Baker Henry V , Sobel Eric , Morel Laurence 
Published: January 2023

Abstract
Systemic Lupus Erythmatosus (SLE) is an autoimmune condition of complex etiology involving genetic susceptibility and environmental factors. CD4+ Helper T-Cells provide co-stimulation to B-Cells to facilitate the production of a large repertoire of high affinity autoantibodies against numerous self-antigens such as dsDNA, histones, and snRNPs. Microarray analyses have been utilized previously to interrogate relevant pathways in disease pathology based on mRNA expression differences in T-Cells from healthy donors and SLE patients. Elevated levels of the E3 ubiquitin ligase MDM2 have been reported in immune cells of MRL.lpr mice and linked to resistance to activation-induced cell death (AICD), but the role of MDM2 in CD4+ T-Cells of human SLE subjects remains unclear. Here, we provide evidence for increased expression of MDM2 in CD4+ T-Cells of human SLE CD4+ T cells and a spontaneous genetic murine model of lupus, NZM2410 derived triple congenic (TC). Moreover, our data also support reduced AICD as a direct consequence of high MDM2. MDM2 has potential roles in the proteasome/ubiquitination pathways as well as inhibitory interactions with apoptotic regulators such as p73 and p53. Further work is needed to elucidate the contribution of this proto-oncogene to autoimmunity in humans and its suitability as a target for therapeutic intervention.
Classical and monocyte-derived DCs require distinct transcriptional programs for cross-presentation.
Authors: Briseno Carlos G , Haldar Malay , Kretzer Nicole M , Wu Xiaodi , Durai Vivek , Theisen Derek , Grajales-Reyes Gary E , Bagadia Prachi , Murphy Theresa L , Murphy Kenneth M 
Published: January 2023

Abstract
Classical DCs (cDCs) and monocyte-derived DCs (Mo-DCs) cross-present cell associated antigens, but whether these cells use a universal program for this process is unknown. In examining the requirements for cross-presentation by Mo-DCs, we discovered that TremL4 identifies two Ly-6Chimonocyte populations, of which only Ly-6ChiTremL4− monocytes can differentiate into Zbtb46+ Mo-DCs in response to GM-CSF and IL-4 in vitro. By contrast, Ly-6Chi TremL4+ monocytes lost Mo-DC potential and instead were committed to development of Ly-6Clo TremL4+ monocytes. Further, we found that differentiation of monocytes with GM-CSF required addition of IL-4 to generate Zbtb46+ Mo-DCs that cross-presented as efficiently as CD8α+ cDCs in vitro. However, unlike CD8α+ cDCs, Mo-DCs required only IRF4, and not Batf3, to cross-present cell-associated antigens. Further, Irf4−/− monocytes treated with GM-CSF and IL-4 could not differentiate into Zbtb46+ Mo-DCs, and instead developed into macrophages. Thus, distinct transcriptional programs are used by CD8α+ cDCs and Mo-DCs for cross-presentation which may drive different antigen-processing pathways.
Galectin-7 regulates infiltration of alternatively activated macrophages into the central nervous system
Authors: Zangbede Fredice Quenum , Chauhan Arun , Sharma Jyotika , Mishra Bibhuti B 
Published: January 2023

Abstract
Alternatively activated macrophages (M2 MΦ) function to dampen host inflammatory responses and promote wound healing and tissue repair. As the blood brain barrier (BBB) restricts the flow of cells into the brain, understanding how M2 MΦ extravagate into the central nervous system (CNS) is of great interest. In a mouse model of neurocysticercosis (NCC) we previously demonstrated that M2 MΦ are essential in containing neuropathology in helminth infected CNS. Analysis of helminth infected mice revealed an abundant expression of galectin-7 that recognize galactose moieties in brain endothelial cells. The Galectin-7−/− NCC mice displayed a reduced accumulation of M2 MΦ in parasite infected brain. This reduction in M2 MΦ numbers in the CNS was correlated with an increased neuropathology and shortened survival. The use of adoptive transfer of fluorescent labeled cells demonstrated a decreased influx of M2 MΦ into the CNS of helminth infected NCC brains. The use of in-vitro transmigration assay conclusively demonstrated a key function of Galectin-7 expressed on endothelial cells in centrally regulating M2 MΦ entry into the CNS.
ENU-induced C-terminal truncation of Runx3 in mice enhances maintenance of memory T cells through upregulation of IL-15 expression
Authors: Su Yu-Chia , Chen Yi-Ting , Chang Mei-Ling , Cheng Bing-Ho , Kung John T 
Published: January 2023

Abstract
Immunological memory provides faster and stronger immune responses to protect host from infectious pathogens and tumor cells. T cell memory is a major part of immunological memory, and plays an important role to eliminate tumor cells or cells infected by intracellular pathogen. Cytokines including IL-15, IL-7 and IL-4 have been reported to enhance the generation or maintenance of memory T cells. IL-15 enhances homeostatic proliferation and survival of memory CD8+ T cells. An ENU-affected mouse pedigree carried a Tyr301stop point mutation of Runx3, which resulted in a truncated form of Runx3. These mice started to show spontaneous diarrhea after weaning (spontaneous colitis, SC). SC mice also expressed CD4-derepression in the CD8+ T cells, and loss of memory phenotype CD8+ T cells. SC CD8+ T cells showed proliferation deficiency and decreased memory CD8+ T cell precursors after activation and also had poor response to IL-15-induced proliferation. However, SC host mice enhanced in vivo long-term survival of activated WT CD8+ cells through improvement of homeostatic proliferation. This improvement of homeostatic proliferation was due to elevated serum IL-15 levels. In summary, C-terminal truncated Runx3 in mice results in upregulation of IL-15 expression and provides enhanced homeostatic environment for memory CD8+ T cells; however, CD8+ T cells have intrinsic memory defect. Thus, the SC mouse model is a valuable tool for investigations on the effect of immune system upon spontaneous colitis.
TCR signal strength and antigen affinity modulate CD8+ memory T Cell development
Authors: Solouki Sabrina , Huang Weishan , August Avery 
Published: January 2023

Abstract
CD8+ T cells play a critical role in adaptive immunity by maintaining the ability to differentiate into CD8+ memory T cells. During an intracellular infection, CD8+ T cells pass through several characteristic phases before becoming mature memory cells. Initial antigen stimulation causes naïve CD8+ T cells to clonally expand and differentiate into short-lived effector cells (SLECs). Subsequently, SLECs undergo a contraction phase to give rise to memory precursor effector cells (MPECs); 5–10% of these MPECs survive the initial contraction phase from SLECs to further develop into CD8+ memory T cells. We have shown that the non-receptor tyrosine kinase Itk, which regulates TCR signal strength, can significantly suppress CD8+ memory T cell development. We hypothesize from that TCR signal strength may function synergistically with antigen affinity to regulate development of memory CD8+ T cells. We are testing this hypothesis using Itk deficient OT-1 TCR transgenic mice, in which CD8+ T cells are engineered to be specific for the Ovalbumin (Ova) protein but exhibit reduced TCR signaling, adoptive transfer of donor naïve CD8+ T cells into marked recipient mice, followed by an infection with recombinant Listeria monocytogenes expressing Ova peptide variant epitopes for CD8+ T cells. Using this model, we can quantitatively determine how TCR signal strength intersects with TCR affinity to control memory development. Our findings suggest that TCR signal strength and TCR affinity separately regulate CD8+ memory development. This data holds societal impact and promise for the advancement of rational vaccine development.
Treatment with rifampicin ameliorates atopic dermatitis-like skin disease in NC/Nga mice through mast cell inactivation
Authors: Kang Tae Jin , Kim Seung Hyun , Lee Ki Man , Lee Geum Seon , Seong Ju-Won 
Published: January 2023

Abstract
Atopic dermatitis (AD) is a common inflammatory skin disorder mediated by inflammatory cells such as macrophages and mast cells. Rifampicin is a major drug for treatment of tuberculosis. Recently it was reported that rifampicin has anti-inflammatory and immune suppressive activity. We herein investigated the effect of rifampicin on atopic dermatitis in NC/Nga mouse model. AD was induced by treatment of 1-chloro 2, 4-dinitrobenzene (DNCB). And then mice were treated with rifampicin by oral administration and were observed to relieve the diverse symptoms. The severity score and scratching behavior were alleviated in rifampicin-treated groups. Serum IgE and IL-4 levels were also decreased in rifampicin-treated groups. We next examined if rifampicin has anti-atopic activity via the suppression of mast cell activation. Rifampicin suppressed the release of β-hexosaminidase and histamine from human mast cell (HMC)-1 cells stimulated with compound 48/80. Treatment of rifampicin inhibited secretion of inflammatory mediators, such TNF-α and PGD2, in mast cells activated by compound 48/80. The mRNA expression of COX-2 was reduced in the cell treated with rifampicin at a dose-dependent manner. These results suggest that rifampicin can be used to treat atopic dermatitis.