bluuebunny/crossref_metadata_2025_split huggingface dataset:
First dose infusion reaction during anti-CD20 monoclonal antibody therapy in chronic lymphocytic leukemia associates with high IP-10 levels amid cytokine release syndrome
Authors: Chu Charles C , Moore Jeremiah E , Bloom Paige C , Bruno Jennifer E , Quataert Sally A , Mosmann Tim R , Jaimes-Delgadillo Nydia , Herne Christine Ann , VanDerMeid Karl R , Baran Andrea M , Peterson Derick R , Taylor Ronald P , Elliott Michael Rusty , Wallace Danielle S , Barr Paul M , Zent Clive S 
Published: August 2023

Abstract
Intravenous (IV) anti-CD20 monoclonal antibody (mAb) therapy for chronic lymphocytic leukemia (CLL) patients often produces a first dose infusion reaction (FDIR) within the first 2 h that requires careful monitoring to avoid serious complications and fatalities. To better understand FDIR, we studied blood samples collected from 37 treatment-naïve CLL patients in our clinical trial NCT03788291 undergoing IV treatment with 50 mg of anti-CD20 mAb (rituximab). We analyzed four time points: baseline (prior to infusion), 1 h later (during infusion), at the end of infusion (~2.5 h) and at 48 h. Infusion reactions (CTCAE (v5) grade ≥2 events) were managed by interrupting the infusion and with symptomatic treatment. 24 (65%) patients had a FDIR and all patients completed the infusion.
Patient and CLL characteristics including measures of disease severity (Rai stage, IGHV mutation status, cytogenetic defects) did not correlate with FDIR. High levels of CLL cells and/or CD20 and their subsequent depletion resulting in decreased serum mAb and/or complement are thought to be risks for FDIR. However, measurements of these parameters did not correlate. Induction of cytokine release syndrome (CRS) may correlate with FDIR. However, CRS was observed in all samples after mAb infusion. The only significant associations with FDIR were higher levels of IP-10, IL-6, and IL-8, with IP-10 most significant. Anti-CD20 mAb activated cytotoxic effector cells, such as tissue-resident macrophages that ingest CLL cells via antibody-dependent cellular phagocytosis (ADCP), may be responsible for these events leading to FDIR. A mouse model of anti-CD20 mAb FDIR and in vitro ADCP cell systems will be useful to further understand the biology of FDIR.
Supported by funding from Acerta/AstraZeneca, the Cadregari Foundation, a generous donation by Elizabeth Aaron, and the NIH NCI grant number R21CA267040.
Mitochondrial translation inhibition in CD4+T cells selectively sensitizes the Th2 subset to increased cell death
Authors: Jawla Neha , Arimbasseri Aneeshkumar 
Published: August 2023

Abstract
Upon stimulation with antigen, resting T cells undergo extensive proliferation followed by differentiation into effector cells and long-lived memory cells. Upregulation of mitochondrial oxidative phosphorylation (OXPHOS) is essential for the activation and proliferation of resting T cells. Mitochondrial DNA encodes 13 proteins, which are integral parts of the complexes that form the mitochondrial respiratory chain. Since mitochondrial ribosomes are evolutionarily similar to bacterial ribosomes, antibiotics targeting bacterial ribosomes inhibit mitochondrial protein synthesis as well. But how these antibiotics affect T cell proliferation and differentiation is not well understood. To address this, we used chloramphenicol to inhibit mitochondrial translation during the activation of naive murine CD4+T cells in Th1 or Th2 polarizing conditions. Cell proliferation and effector functions were reduced in both Th1 and Th2 cells when activated in presence of chloramphenicol. Moreover, chloramphenicol significantly altered metabolic reprogramming in Th1 and Th2 cells indicated by a lower rate of OXPHOS and upregulation of glycolysis to maximum levels. Interestingly, inhibition of mitochondrial translation resulted in increased apoptosis following activation specifically in the Th2 effector subset. Th2 cells displayed a significant increase in caspase 3/7 activity upon mitochondrial translation inhibition. RNA sequencing analysis identified the upregulation of Bim and Puma in Th2 cells, two pro-apoptotic proteins that are known to be upregulated in response to metabolic stress. These results show that Th2 cells specifically undergo apoptosis in response to antibiotics that target mitochondrial translation.
Support from ICMR, NII-DBT
Translation inhibitor PDCD4 promotes CD8+ T cell proliferation during antiviral response
Authors: Xie Xiangfei , Araki Koichi 
Published: August 2023

Abstract
CD8+ T cell clonal expansion is critical for controlling intracellular infections and tumors. Thus, unravelling the mechanisms that regulate CD8+ T cell proliferation are imperative to improve vaccine design and immunotherapy. However, the molecular mechanisms that govern CD8+ T cell proliferation are still not fully understood. PDCD4 (Programmed cell death 4) was shown to inhibit translation by sequestering mRNA helicase eIF4A, which leads to translation inhibition of genes involved in cell proliferation. Despite the well-characterized anti-proliferative role of PDCD4, our studies suggest that PDCD4 promotes CD8+ T cell proliferation during the expansion phase of acute LCMV infection. We find that PDCD4 over-expressed Ag-specific CD8+ T cells have higher proliferation rate which leads to increased cell number compared to control Ag-specific CD8+ T cells. Consistent with the over-expression results, PDCD4 knocking-down Ag-specific CD8+ T cells undergo less cell proliferation, resulting in reduced clonal expansion compared to controls. Interestingly, contrary to the paradigm that increased proliferation generates more short-lived effector cells, CD8+ T cell proliferation mediated by PDCD4 does not skew the differentiation of short-lived and memory precursor effector cells. This PDCD4 mediated CD8+ T cell proliferation is also confirmed by over-expression of a constitutively active form of PDCD4 which resists degradation by CD8+ T cell endogenous ubiquitin pathway. In conclusion, our work has identified a novel pro-proliferative role of PDCD4 during CD8+ T cell response.
Supported by grants from NIH (R01 AI139675)
Epigenetic changes program innate immunity during Staphylococcus aureus craniotomy infection
Authors: Van Roy Zachary , Kielian Tammy L 
Published: August 2023

Abstract
A craniotomy is performed to access the brain for the treatment of tumors, epilepsy, or hemorrhage. Despite advances in surgical techniques, infections occur in 1–3% of cases, half of which are caused by Staphylococcus aureus (S. aureus). Since epigenetic mechanisms are critical for regulating leukocyte activation, we examined whether S. aureus drives epigenetic modifications to regulate immune cell function during craniotomy infection. A high-throughput screen of an epigenetic compound library using primary mouse microglia identified BET protein family members and histone deacetylases (HDACs) as critical for regulating TNF, IL-6, and IL-10 production by microglia, macrophages, neutrophils, and granulocytic myeloid-derived suppressor cells (G-MDSCs). Various class I HDACs were increased in these cell types following both in vitro and acute S. aureus infection in vivo. However, at later timepoints in vivo, HDAC2 expression was reduced, illustrating the importance of the brain microenvironment for genomic organization. Microparticle delivery of HDAC and BET inhibitors in vivo significantly increased bacterial burden concomitant with decreased inflammatory mediator production, revealing a critical role for epigenetic mechanisms in bacterial containment. Collectively, our data suggest that inflammatory mediator production is regulated by histone acetylation during craniotomy infection and aberrant epigenetic regulation may be important for promoting bacterial persistence.
Work supported by NINDS R01 NS107369 and T32 NS105594.
Mitochondrial metabolic flexibility is critical for CD8 T cell anti-tumor immunity
Authors: Chen Chao , Qu Cheng-Kui 
Published: August 2023

Abstract
Mitochondria utilize various substrates for energy production and intermediatory metabolism to support cellular activities. Cytotoxic CD8 T cells in different functional states during the life cycle have distinct metabolic requirements, and they experience dynamic changes in energy sources and oxygen levels in different microenvironments. The significance of mitochondrial metabolic flexibility for CD8 cell immune responses remains poorly understood. Here we report that the deletion or pharmacological inhibition of PTPMT1, a mitochondria-based phosphatase, significantly decreased effector cell specification and clonal expansion from activated CD8 cells. In addition, PTPMT1 deletion accelerated CD8 T cell exhaustion and impaired stem-like T cell maintenance, leading to increased tumor growth. PTPMT1 depletion also suppressed CD8 T cell anti-viral responses. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection – the utilization of pyruvate, a major mitochondrial substrate derived from glucose (the simple carbohydrate), was inhibited whereas fatty acid and glutamate utilizations were enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress and apoptosis in PTPMT1 knockout CD8 cells. The impact of the biased mitochondrial fuel selection on CD8 T cells was further verified in mitochondrial pyruvate carrier/transporter (MPC) knockout and pharmacological inhibition models. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8 T cell anti-tumor immunity.
National Institutes of Health grants HL162725 and CA275964
Pim2 negatively regulates T-cell immune responses through modulating autophagy
Authors: Tian Linlu , Wu Yongxia , Choi Heejin , Yang Kaipo , Yu Xue-Zhong 
Published: August 2023

Abstract
Pim kinases affect cell survival, cell proliferation, transcriptional activation, and protein translation by phosphorylating various target substrates. We previously showed that Pim2 plays a distinct role from Pim1 and Pim3, and negatively regulates T-cell allogeneic response and anti-tumor immunity. Pim2 was reported to promote the induction of autophagy in cancer cells, a cellular process that critically impacts T-cell effector function, survival and memory formation. We hypothesize that Pim2 constrains T-cell immune responses through modulating autophagy. Using western blot and electron microscopy, we evaluated the effect of Pim2 on autophagic flux in resting and activated T cells. Pim2 deficiency in T cells attenuated LC3 lipidation, P62 degradation as well as autophagosome formation, suggesting that Pim2 facilitates autophagy in T cells. Mechanistically, Pim2 directly bound with P62 and loss of Pim2 led to accumulation of P62 which further blocked autophagic flux in T cells. Furthermore, augmentation of autophagy via overexpressing Atg5 or metformin treatment reduced effector cytokine production in Pim2-deficient T cells in vitro and reversed the heightened ability of Pim2-deficient T cells for inducing graft-versus-host disease and for controlling breast cancer growth in vivo. Taken together, Pim2 is a key promotor of autophagy in T cells and targeting Pim2 to suppress autophagy may represent a promising strategy to improve T-cell effector function in cancer immunotherapy.
The work was supported by NIH grants: R01 CA258440 and R21 CA263140.
Sin3A Controls FoxP3+ Treg Production, Stability and Function
Authors: Christensen Lanette M , Akimova Tatiana , Han Rongxaing , Wang Liqing , Samanta Arabinda , Hancock Wayne W 
Published: August 2023

Abstract

Purpose
Foxp3 T-regulatory (Treg) cells are key to immune homeostasis but the function of paired amphipathic helix protein, Sin3a, is unknown.

Methods
We studied the effects of Sin3a deletion in Treg cells.

Results
Sin3a−/− FoxP3Cre mice died from severe autoimmunity by 2–3 weeks of birth. Mice had enlarged lymph nodes, severe inflammation in lungs, skin, livers and kidneys and autoantibodies to islet cells, striated muscles, keratin, endomysium and gastric parietal cells. Percentages of FoxP3+ Tregs in LNs and spleens were lower (p values ranging from &gt;0.01 to &gt;0.0001) than controls and FoxP3 mRNA expression (&gt;20-fold) and FoxP3 protein per Treg (&gt;3-fold) were also significantly reduced in Sin3a−/− mice. Reduction of FoxP3+ Tregs in the periphery of Sin3a−/− FoxP3cre mice was largely due to the loss of FoxP3, determined by an increase of peripheral ex-Tregs as compared to WT (p&lt;0.001 in sLN and spleens) within Sin3a−/− FoxP3Cre tdTomatoROSA26 lineage tracing mice. Increased mRNA expression of pro-apoptotic genes, decreased mRNA expression of anti-apoptotic genes, and increased presence of Annexin V on the cell surface indicate that apoptosis also contributed to peripheral Treg reduction. Sin3a−/− Tregs produced increased amounts of granzyme B, IFN-γ and IL-2 (12–45% of cells) and had impaired suppressive function (p&lt;0.01). Sin3a was also essential for peripheral iTreg conversion since CD4+CD25− cells from Sin3a−/− FoxP3Cre mice lacked ability to convert to FoxP3+ iTregs ex vivo.

Conclusions
The nuclear co-regulator, Sin3a, helps maintain the unique homeostatic properties of Treg cells. Therapeutic modulation of Treg functions may be possible by pharmacologic targeting of components within the Sin3a complex.
Epigenetic Memory of COVID-19 in Innate Immune Cells and Their Progen-itors--
Authors: Cheong Jin Gyu G 
Published: August 2023

Abstract
Through epigenetic mechanisms, systemic inflammation may trigger innate immune memory and persistent changes in hematopoietic cells; however, it has been difficult to investigate these phenotypes in the context of human disease, such as severe coronavirus disease 2019 (COVID-19). We developed a new workflow to isolate circulating hematopoietic stem and progenitor cells (HSPC) from peripheral blood, combining single-cell RNA/ATAC-seq. With this method, we were able to capture the diversity of circulating HSPC as seen in bone marrow, allowing for the non-invasive investigation of hematopoiesis as well as epigenomic changes after COVID-19. Following severe COVID-19, we observed both transcriptomic and epigenetic changes in HSPC and its progeny innate immune cells, and they persisted for months to a year. Different transcription factor activities (including IRF, AP-1, and CTCF) were associated with these alterations, which altered the regulation of inflammatory programs. Severe COVID-19 patients’ HSPC displayed long-lasting increases in myelopoiesis and granulopoiesis, and circulating monocytes responded more strongly to subsequent stimulation. We found that epigenomic changes in HSPC were retained and passed onto differentiated progeny innate immune cells. In addition, we demonstrate that administration of an anti-IL-6 blockade during acute severe COVID-19 can normalize the persistent phenotypes, suggesting that IL-6 plays a role in the development of epigenetic memory. In conclusion, epigenetic reprogramming of HSPC may underlie altered immune function subsequent to infection and has broad applicability, particularly for millions of COVID-19 survivors with incomplete recovery.
Novel function for gluconeogenic enzyme, FBP1, in T cell activation and expansion
Authors: Kelekar Ameeta , Sha Ruohan , Yang Tingyuan , Bapat Aditi , Park Meeyeon , Simon M Celeste , Yong Jeongsik 
Published: August 2023

Abstract
During an immune response, naïve T lymphocytes undergo rapid clonal expansion and must reprogram their metabolism to meet high energetic and biosynthetic demands. The sudden increase in metabolic activity associated with a proliferative burst generates reactive oxygen species (ROS) increasing intracellular oxidative stress, which can disrupt homeostasis or trigger cell death, unless properly regulated. Our studies show that a constitutively active isoform of gluconeogenic enzyme, fructose 1,6-bisphosphatase 1 (FBP1), facilitates re-entry of glucose carbons into the pentose phosphate pathway to ensure the sustained production of NADPH for redox homeostasis and lipid synthesis in stimulated T cells as they transition to a phase of rapid growth, and is essential for their unperturbed clonal expansion and for an effective immune response. Wildtype (wt) FBP1, which catalyzes hydrolysis of fructose-1,6 bisphosphate in an irreversible reaction, has a C-terminal catalytic domain and an inhibitory N-terminal regulatory domain. We demonstrate that a short isoform of FBP1 representing the catalytic domain is induced in human T cells within 24 hours of co-stimulation. The short isoform, FBP1-CD, is the product of an alternatively spliced transcript and is resistant to inhibitors that suppress activity of wt FBP1, which harbors the regulatory domain. FBP1-CD levels and enzyme activity are significantly reduced 5 days post-stimulation, correlating positively with proliferation and inversely with ROS and apoptosis in T cells. In addition to new insights into immune regulation, our studies reveal a broader role for FBP1 in regulating proliferative metabolism and offer a rational explanation for the suppression of FBP1 in solid tumors.
Supported by grant from NIH (R21 AI168777)
Desmosterol plays an atheroprotective role in B cells through B cell subset differentiation and B cell activation
Authors: Ma Shelby , Moriarty Alina , Keeter W Coles , Stahr Natalie Ann , Kirk Cassandra Lee , Waseem Tayab 
Published: August 2023

Abstract
Atherosclerosis is a complex, inflammatory disease associated with lipid accumulation, vascular dysfunction, and inflammatory immune response in the large and medium sized arteries. B cell roles in atherosclerosis are subset specific. Increasing evidence suggests a role for glucose metabolism in shaping the immune response, but less is known about cholesterol metabolism and adaptive immunity. Desmosterol, a precursor of cholesterol in the Bloch cholesterol biosynthesis pathway, serves as a negative regulator of macrophages. To date, the effect of intermediates of cholesterol metabolism on MF functions is an area of intensive study, but little is known about effects of desmosterol in B cell subset-specific functions. We have generated a mouse model with overexpression of 24-dehydrocholesterol reductase (DHCR24), an enzyme that converts desmosterol into cholesterol, specifically in B cells using the cre/flox system crossed with an atherosclerotic mouse model (Dhcr24fl/flCd19cre/+Ldlr−/− mice). The deletion of DHCR24 results in reduction of desmosterol specifically in B cells. After fed a Western diet for 12–16 wks aortas were collected to assess lesion formation and spleens were collected to assess B cell subset distribution, activation, and functions by FACs. We demonstrate that overexpression of DHCR24 in B cells leads accelerated lesion formation. This was accompanied by increased BCR-induced B cell activation via the increased Ca2+ flux along with increased FO B cells and decreased MZ B cells. This suggests that desmosterol plays a suppressive role in B cell activation and plays a role in B cell subset differentiation and activation, highlighting a role of desmosterol as a regulator of B cell functions.
Distinct domains in the transcription factor Runx3 mediate differential antiviral CD8 T cell phenotypes
Authors: Albao Dominic S , Pipkin Matthew E 
Published: August 2023

Abstract
Runx3 is one of three Runt-family transcription factors (TF) that control gene expression by modifying chromatin structure. Upon initial T cell receptor stimulation, Runx3 drives chromatin accessibility found in mature circulating and tissue-resident memory CD8 T cells. Runx3-deficient cells preferentially develop a KLRG1hi CD127lo terminal effector (TE) phenotype, whereas Runx3 overexpression promotes formation of KLRG1lo CD127hi classical memory precursor (MP) cells and KLRG1hi CD127hi double positive (DP) effector cells during the effector phase. Runt-family TFs harbor activation, inhibition, and VWRPY domains that interact with distinct chromatin modifying proteins, but their individual contributions to Runx3-driven phenotypes in effector CD8 T cells are unresolved. Here we examined Runx3-deficient CD8 T cells complemented with wildtype or Runx3-domain deleted mutants during viral infection. The activation and VWRPY domains were each required to repress the TE cell phenotype. However, the activation, but not VWRPY domain, was necessary to repress high T-bet expression. Moreover, the larger gene expression pattern resulting from complementation with the VWRPY mutant was generally similar to that of wildtype Runx3. In addition, we found that wildtype Runx3 repressed the TF Tox and upregulated PD-1 and Tim-3, which required its inhibition domain. Runx3 lacking its inhibition domain also generated more MP cells and more highly induced CD127 compared to wildtype Runx3. These results indicate that distinct domains in Runx3 mediate differential control of gene expression in effector CD8 T cells, and might suggest avenues for targeting Runx3 domains to elicit specific memory T cell phenotypes.
Supported by grants from NIAID (R01 AI095634, P01 AI145815)
Glucocorticoids regulate the human non-coding genome
Authors: Kwiat Robert Ernest , Tran Thai , Cao Qilin , Gadkari Manasi , Randazzo Davide , Franco Luis M 
Published: August 2023

Abstract
Glucocorticoids (GCs) are the most commonly used anti-inflammatory and immunosuppressive drugs. However, most of the work on this class of drugs has focused on their relationship to the coding genome. It has been demonstrated in recent years that non-coding genes can play important biological roles. Thus, we performed total RNA-seq and small-RNA-seq in 9 primary human cell types: B cells, CD4+ T cells, monocytes, neutrophils, endothelial cells, fibroblasts, myoblasts, osteoblasts, and preadipocytes, treated in vitro with the GC methylprednisolone. We found that the response of lncRNA genes to GCs appears to be strong and cell type-dependent, with hematopoietic cells being more responsive to GCs than non-hematopoietic cells. Among GC-responsive lncRNAs, the intergenic and RNA host subtypes are overrepresented, while antisense lncRNAs are underrepresented. GC regulation of miRNAs appears to be limited to those that are part of a larger transcript. We generated a global map of GC-responsive lncRNAs and microRNAs in the 9 cell types, and an interactive web application to allow exploration of our results. We identified the lncRNA WAKMAR2 as a GC-induced gene that may play a role in GC action in CD4+ T cells and monocytes. WAKMAR2 has been shown to influence the expression of inflammatory cytokines in non-hematopoietic cells. Single-molecule RNA FISH revealed that, in human monocyte-derived macrophages, WAKMAR2 transcripts are primarily cytoplasmic. Ongoing work is aimed at determining whether WAKMAR2 is in fact a GC-induced negative regulator of inflammatory responses in human primary cells.