bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of natural killer cell activity in HIV infections, aging, and breast cancer survival
Authors: Williams R Michael , Zuniga Joaquin , Granados Julio , Yunis Edmond J. 
Published: January 2023

Abstract
Natural killer cell activity participates in the elimination of tumors and virus infections. Data presented here include their role in a virus infection (HIV), metastatic breast cancer, and aging per se. We have analyzed two gene segments MHC HLA class I ligands and NK receptors Each have single amino acid differences. Together these alleles can identify long term survivors. Homozygosity of HLA–Bw4 supertype in HIV progression has been described. Since HLA-KIR genetic interactions of HLA-Bw4 with KIR (3DS1) only included Bw4, with the exception of B*27 and B*44 that use different mechanism of protection, on the clinical outcome of HIV infection, NK–ligand interactions (NKG2A-HLA-E with HLA class I leader peptides) explain the long term non-progressors (LTNP) to AIDS. HLA-B alleles have Methionine (Met) or Threonine (Thr) at second position (P2) of their leader peptide. HLA-Bw4 alleles, with exception of B*38, encode leader peptide with Thr at P2 and HLA-Bw6 genes that encode Met at P2 are B*07, B*08 and B*14. All others have Thr at P2. Comparisons of the Thr in LTNP with progressors, up to 15 years. with non-infected Caucasian controls were significant. Also, aged Mexicans demonstrated significant increase of homozygosity of Thr at P2 and Mexican patients with metastatic breast cancer were studied 10 years after treatment with surgery and chemotherapy,
The 39 survivors demonstrated significant increase of homozygosity of Thr at P2 compared to controls without cancer and the 37 non survivors. These findings need to be studied in different malignancies and different ethnicities as well as in mouse models. Our findings support the immunogenetic theory of cancer and aging.
Production of Peanut-Specific IgE in a Food Allergy Model Is Promoted by T Follicular Regulatory Cells Via an IL-10-Dependent Pathway
Authors: Xie Markus Ming , Liu Hong , Yang Kai , Dent Alexander 
Published: January 2023

Abstract
T follicular regulatory (TFR) cells are a specialized subset of Foxp3+ T cells found within the germinal center (GC) reaction and its role remains controversial. Here, we have used a peanut allergy model in mice to examine the role of TFR cells in controlling the production of antigen-specific IgE and IgE-controlled anaphylaxis. Using a mouse model with a specific loss of TFR cells (Foxp3-cre Bcl6-flox mice), we found TFR cells play an essential role in promoting and maintaining GC B cells, IgE production and anaphylaxis. Compared to control mice, TFR-deficient mice lacked circulating peanut-specific IgE four weeks after the priming period and anaphylactic responses were significantly weakened. The loss of IgE in TFR-deficient mice coincided with a marked decrease in GC B cells and peanut-specific IgG1. Similarly, deletion of regulatory T cells using FOXP3DTR mice abolished peanut-specific IgE and IgG1 responses. We identified a positive role for TFR cells in the IgE response using Foxp3-cre Pten-flox mice, which have augmented TFR cell responses, higher peanut-specific IgE and increased GC B cells. Mechanistically, TFR cells require Blimp1 controlled IL-10 to promote GC B cell survival and IgE production. Further studies using mice deficient of IL-10Ra (Mb1-cre Il10ra-flox mice) showed IL-10 signaling was pivotal for GC B and Ab responses. Blocking IL-10 signals in vivo mimicked the loss of IgE levels in TFR-deficient mice and rescued mice from anaphylaxis. Our data unexpectedly show that TFR cells have a critical helper function in the production of GC-dependent IgE, in part by producing IL-10. These studies have provided greater understanding of how allergic immune responses are controlled by the GC reaction.
Activated Plasmodium-specific CD8 T cells find liver stages mostly randomly
Authors: Zenkov Viktor S , Ganusov Vitaly V , O'Connor James , Cockburn Ian A 
Published: January 2023

Abstract
Malaria is a major infectious disease, with 500,000 people dying every year. Malaria infection starts when an infected mosquito injects malaria sporozoites during feeding which migrate to the liver and form liver stages. Elimination of liver stages is a major feature of CD8 T cell-based malaria vaccines. It is established that vaccines inducing high numbers of memory CD8 T cells are capable of eliminating all liver stages, preventing clinical malaria. However, how CD8 T cells are capable of doing that in the 48-hour liver stage in mice remains unclear. One possibility is that as sporozoites invade hepatocytes from the blood, they induce local inflammation, acting as an attraction signal for T cells. We performed experiments in which fluorescent-labeled Plasmodium sporozoites and Plasmodium-specific and non-specific CD8 T cells were tracked in mouse livers using intravital microscopy. To analyze the data we used three metrics to measure attraction of T cells to the infection site based either on angles or distances from a T cell to the parasite. We found that for the majority of imaged T cells, there is no evidence of attraction to the parasite, indicating that in this experimental system, vaccine-induced CD8 T cells locate the infection site randomly. By modeling T cells searching for the infection site and utilizing experimentally measured speeds of T cell movement in the liver, we found that if enough memory CD8 T cells are present in the liver, all parasites can be found within 48 hours after sporozoite injection. Taken together, our results suggest that memory CD8 T cells in the liver perform the search for infection randomly, precluding the need to find specific signals and receptors of T cell attraction to the infection site.
Costimulation of type-2 innate lymphoid cells by GITR promotes effector function and ameliorates type 2 diabetes
Authors: Galle Lauriane , Sankaranarayanan Ishwarya , Hurrell Benjamin P , Howard Emily , Lo Richard , Maazi Hadi , Lewis Gavin , Banie Homayon , Epstein Alan L , Hu Peisheng , Rehan Virender K , Gilliland Frank D , Allayee Hooman , Soroosh Pejman , Sharpe Arlene H , Akbari Omid 
Published: January 2023

Abstract
Metabolic syndrome is characterized by disturbances in glucose homeostasis and the development of low-grade systemic inflammation, which increase the risk to develop type-2 diabetes mellitus (T2DM). Type-2 innate lymphoid cells (ILC2s) are a recently discovered immune population secreting Th2-cytokines. While previous studies show how ILC2s can play a critical role in the regulation of metabolic homeostasis in the adipose tissue, a therapeutic target capable of modulating ILC2 activation has yet to be identified.
We found that GITR, a member of the TNF superfamily, is expressed on murine adipose tissue ILC2s and its engagement on activated ILC2s induces Th2-cytokine secretion. Moreover, we showed that GITR engagement on ILC2s improves glucose homeostasis resulting in both protection against insulin-resistance onset and amelioration of established insulin-resistance. Our adoptive transfer studies demonstrated that this protective effect is dependent on ILC2-derived Th2-cytokines, particularly IL-13. Transcriptome analysis demonstrated that GITR agonist activates the NF-κB signaling pathway and inhibits ILC2 apoptosis, altogether favoring ILC2 survival and activation. Finally, we also found that GITR is expressed on human adipose tissue resident ILC2s and GITR engagement robustly induces Th2-cytokine.
Together, these results highlight the critical role of GITR as a novel therapeutic molecule against T2DM and its fundamental role as an immune checkpoint for activated ILC2s.
Natural killer cell inhibition of HIV vaccine responses
Authors: Gyurova Ivayla E , McNally Jonathan P , Rydyznski Carolyn E , Waggoner Stephen N 
Published: January 2023

Abstract
There is an increasing appreciation of the ability of natural killer (NK) cells to inhibit adaptive immunity. We previously found that NK cells inhibit antiviral T-cell responses and antibody production during acute virus infection in mice. NK cells also inhibit follicular helper (Tfh) T-cell and germinal center (GC) B-cell responses following immunization with alum-adjuvanted NP-KLH. Of note, NK-cells are linked to a reduced frequency of immunoglobulin heavy chain mutations and impaired affinity maturation of NP-specific GC B cells, indicating that NK cells are important modulators of both the magnitude and the quality of the humoral responses. As a successful HIV vaccine putatively requires more extensive and efficient affinity maturation of HIV-specific immunoglobulin sequences than has been achieved in vaccine efforts to date, we hypothesize that NK-cell suppression of Tfh and GC responses represents a promising target to enhance HIV-specific vaccine responses. To test this hypothesis, we administered a HIV envelope (Env)-expressing vaccinia virus (VACV-Env) to mice depleted or not of NK cells. The absence of NK cells was associated with increased frequencies of HIV-specific GC B cells and elevated production of Env-specific immunoglobulins. The enhancing effect of NK-cell depletion at both priming (VACV-Env) and boosting (Env protein) immunizations was robust. These results are consistent with recent demonstration of an association between NK-cell dysfunction and development of bnAbs in HIV-infected individuals. Thus, NK cells are important regulators of affinity maturation and of HIV-specific antibody responses, suggesting that interventions targeting this NK cell activity could enhance HIV vaccine efficacy.
The lysophosphatidylcholine transporter, MFSD2A, is essential for CD8+ memory T cell maintenance and secondary response to infection
Authors: D'Cruz Louise M , Piccirillo Ann , Hyzny Eric , Menk Ashley , Wallace Callen , Hawse William F , Buechel Heather Marie , Wong Bernice , Foo Juat Chin , Cazenave-Gassiot Amaury , Wenk Markus , Delgoffe Greg M. , Watkins Simon , Silver David 
Published: January 2023

Abstract
Access to nutrients is critical for an effective T cell immune response to infection. Although transporters for sugars and amino acids have previously been described in the context of the CD8+ T cell immune response, the active transport of exogenous fatty acids has remained enigmatic. Here we discovered the sodium-dependent lysophosphatidylcholine transporter, Major Facilitator Super Family Domain Containing 2a (MFSD2A), is upregulated on activated CD8+ T cells and is required for memory T cell maintenance. MFSD2A deficiency in mice resulted in decreased import of lysophosphatidylcholine (LPC) esterified to long chain fatty acids (LCFAs) into activated CD8+ T cells, and MFSD2A deficient cells are at a competitive disadvantage resulting in reduced memory T cell formation and maintenance and reduced response to secondary infection. Mechanistically, import of LPCs was required to maintain T cell homeostatic turnover, that when lost resulted in a decreased memory T cell pool and thus a reduced secondary response to repeat infection.
PU.1 and IRF8 regulate the transcriptional landscapes differently in naïve and activated B cells
Authors: Wang Hongsheng , Li Peng , Lin Jianxin , Oh Jangsuk , Bolland Silvia , Leonard Warren J , Morse Herbert C 
Published: January 2023

Abstract
The Ets family member PU.1 and the IRF family member IRF8 play crucial roles in regulating hematopoietic cell development including B cells. Both factors are constitutively expressed at high levels in B cells and control plasma cell differentiation. IRF8 and PU.1 function either together as a heterodimer or by pairing with other factors to bind target DNA sequences. Several consensus binding sequences for IRF8 and PU.1 have been identified, including the canonical interferon stimulated response element (ISRE) sequence motif (GAAANNGAAA), the Ets-IRF composite element (EICE) (GGAANNGAAA) and the IRF-Ets composite sequence (IECS) (GAAANN[N]GGAA). Although the target genes of IRF8 and PU.1 have been studied previously by chromatin immunoprecipitation (ChIP), the nature and the importance of the motifs engaging both PU.1 and IRF8 in B cells have not been determined. In this study, we performed ChIP-seq using sort-purified naïve follicular B cells from C57BL/6 mice that were either not stimulated or stimulated with anti-IgM plus anti-CD40, which mimic signals for germinal center B cell differentiation. We also integrated our ChIP-seq data with RNA-seq data from B cells deficient for both IRF8 and PU.1, and found that IRF8 and PU.1 regulate gene expression by preferentially binding to the EICE motifs of target genes known to maintain follicular B cell identity, localization, and survival. In contrast, in activated B cells, the binding landscape of IRF8/PU.1 in target genes shifts to IRF8-dominant ISRE motifs, possibly due to elevated expression of IRF8. These results provide new insights into our understanding of the molecular mechanisms underlying the transcriptional control of late stage B cell development.
Temporal dynamics of the serological compartment of rabbit antibody repertoires
Authors: Patel Anand , Bonissone Stefano R , Castellana Natalie 
Published: January 2023

Abstract
Understanding the serum antibody repertoire is an essential first step in improving vaccine design, understanding autoimmune diseases, and discovering drug candidates. Next-generation sequencing (NGS) of peripheral blood mononuclear cells is a common approach to approximate the repertoire; however it is a poor proxy for circulating antibodies. Sampling serum antibodies with mass spectrometry provides orthogonal data - directly querying the repertoire of interest.
In this study, we integrated next-generation sequencing of the B-cell repertoire with mass spectrometry-based proteomic analysis of circulating antibodies in a hyperimmunized New Zealand white rabbit. During a 14 week immunization with 4 boosts, we sampled the B-cell repertoire of blood at multiple time points, as well as the bone marrow and spleen at week 14. At week 14, serum antibodies were enriched for immunogen-specificity using affinity chromatography and subjected to tandem mass spectrometry analysis. We mapped the tandem mass spectra to the antibody sequences in the repertoire to derive a set of clonal lineages and antibodies that are target specific and abundant in serum. We then tracked those lineages across time points and tissues throughout the immunization.
Finally, we sought to determine the fraction of antigen-specific antibodies present in serum but absent from the B-cell derived repertoires. We employed spectral networking to identify novel clonal lineages, and estimate that at least 1/3 of the abundant clones in serum are missing from the repertoire.
Cooperative roles for Aiolos and STAT3 in TH17 differentiation
Authors: Moon Sol C , Sreekumar Bharath , Rasheed Mustafa N , Read Kaitlin , Powell Michael Duane , Oestreich Kenneth J. 
Published: January 2023

Abstract
TH17 cells are a subset of T helper cells involved in mucosal immunity that are defined, in part, by their production of the proinflammatory cytokine IL-17. Dysregulated Th17 cells have been implicated in several autoimmune diseases, such as multiple sclerosis and inflammatory bowel disease. Therefore, there is substantial interest in understanding the mechanisms underlying their differentiation and function. TH17 development requires signals from IL-6 to activate STAT3, which positively regulates the expression of proinflammatory genes including Il17a and Il17f. Our recent work established that the Ikaros Zinc Finger (IkZF) transcription factor Aiolos cooperates with STAT3 to positively regulate gene expression in T follicular helper cells. Given the role of STAT3 in TH17 populations, we hypothesized that Aiolos and STAT3 may also regulate the differentiation of TH17 cells. Here, we find that Aiolos expression is significantly increased in TH17 cells as compared to other T helper cell subsets. Corroborating previously published work, we find that overexpression of Aiolos results in reduced expression of Il2, which negatively regulates the TH17 gene program. Intriguingly, we find that concurrent Aiolos and STAT3 overexpression leads to further repression of Il2, as well as increased expression of the pro-TH17 gene Il6ra. However, expression of Rorc, Il17a, and Il17f were unaffected in this system, suggesting that Aiolos and STAT3 cooperate to regulate cytokine signaling pathways in TH17 cells, rather than ROR gamma t or TH17 effector functions. Collectively, these data suggest that Aiolos and STAT3 may cooperatively regulate TH17 differentiation through a feed-forward, cytokine signaling-mediated mechanism.
Regulation of Tfh cell development through STAT1 signaling
Authors: Qin Lei , Sahoo Anupama , Zhao Yangzhi , Alekseev Andrei , Nurieva Roza I 
Published: January 2023

Abstract
T follicular helper (Tfh) cells play a key role in providing help to B cells during germinal center (GC) reactions. The generation and function of Tfh cells is regulated by multiple checkpoints including their early priming stage in T zones and throughout the effector stage of differentiation in GCs. Signaling pathways activated downstream of cytokine and costimulatory receptors as well as consequent activation of subset-specific transcriptional factors are essential steps for Tfh cell generation. While to date early signaling events for fate committed differentiation of Tfh cells are sufficiently studied, mechanisms allowing Tfh cells to maintain their commitment/programming are still unclear. Here we report that signal transducer and activator of transcription 1 (STAT1) deficiency in CD4+ T cells leads to a diminished number of Tfh cells at day 7 and 14 days after antigen immunization, while at day 3–4, number of Tfh cells was comparable between STAT1-sufficient and STAT1 deficient mice, suggesting the role of STAT1 in Tfh lineage maintenance rather than in Tfh cell priming. In fact, in both mouse and human Tfh cells interleukin (IL)-21 mRNA and protein expression is dependent on the presence of STAT1. Functionally, STAT1 in cooperation with STAT3, Batf, and IRF4 triggers IL-21 production in Tfh cells by directly binding to and activation of the IL-21 gene locus. Moreover, utilizing gene knockout approach, we have determined that Batf is a crucial connector to form STAT1/STAT3/Batf/IRF4 active complex for triggering IL-21 transcription. Our results thus indicate functional contribution of STAT1 towards regulation of IL-21 expression and Tfh lineage maturation/maintenance.
Regulation of T cell activation and pathogenicity by dimeric pyruvate kinase M2 (PKM2)
Authors: Angiari Stefano , Sutton Caroline , Runtsch Marah C , Palsson-McDermott Eva M. , Mills Kingston H.G. , O’Neill Luke A.J. 
Published: January 2023

Abstract
Pyruvate kinase (PK) catalyses the conversion of phosphorenolpyruvate to pyruvate during glycolysis. Previous studies suggested that the PK isoform PKM2 also plays moonlighting activities different from its enzymatic one, such are regulation of gene transcription and protein phosphorylation. PKM2 was previously shown to control macrophage metabolic remodelling and pro-inflammatory potential, but its role in CD4+ T cell biology is poorly understood. In the present work, we report that PKM2 is upregulated in both murine and human CD4+ T cells following activation in vitro. In particular, PKM2 is present in equilibrium between a monomeric, dimeric and tetrameric isoform in T cells, with the dimeric one appearing exclusively upon activation. Treatment of T cells with TEPP-46, an allosteric activator that induces PKM2 tetramerisation and blocks dimer formation, strongly reduces their activation, proliferation and cytokine production through alteration of intracellular metabolism. TEPP-46 inhibits the generation of both T helper 17 (Th17) and Th1 cells, while inducing regulatory T cell development in vitro. Finally, in vivo treatment with TEPP-46 ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. Overall, our results suggest that PKM2 induction and dimerisation are essential steps for T cell activation and pathogenicity, and targeting PKM2 dynamics may have therapeutic utility in T cell-mediated inflammation and autoimmunity.
XL-DNase-seq: Improved footprinting of dynamic transcription factors
Authors: Oh Kyu Seon , Ha Jisu , Baek Songjoon , Sung Myong-Hee 
Published: January 2023

Abstract
As the cost of high-throughput sequencing technologies decreases, genome-wide chromatin accessibility profiling methods such as the assay of transposase-accessible chromatin using sequencing (ATAC-seq) are employed widely, with data accumulating at an unprecedented rate. However, accurate inference of protein occupancy requires higher resolution footprinting analysis where major hurdles exist, including the sequence bias of nucleases and the short-lived chromatin binding of many transcription factors (TFs) with consequent lack of footprints. Here we introduce an assay termed crosslink (XL)-DNase-seq, designed to capture chromatin interactions of dynamic TFs. Mild crosslinking improved the detection of DNase-based footprints of dynamic TFs but interfered with ATAC-based footprinting of the same TFs. XL-DNase-seq may help extract novel gene regulatory circuits involving previously undetectable TFs. The DNase-seq and ATAC-seq data generated in our systematic comparison of various crosslinking conditions also represent an unprecedented-scale resource derived from activated mouse macrophage-like cells which share many features of inflammatory macrophages.
A New crucial role for complement receptor CD46 in chromatin packaging and direct gene regulation
Authors: Singh Parul , Kunz Natalia , Le Friec Gaelle , Kazemian Majid , Afzali Behdad , Lavender Paul , Kemper Claudia 
Published: January 2023

Abstract
Chromatin is the condensed form of DNA ‘packaged’ by positively charged histones in the nucleus. Post-translational modifications of histones regulate nucleosome dynamics, chromatin accessibility and gene expression. Signals mediated by autocrine activation of the human-specific complement regulator/receptor CD46 during T cell receptor stimulation are vital to Th1 induction in CD4+ T cells. CD46 is expressed in different isoforms that arise through alternative-splicing of a single gene - with two distinct cytoplasmic tails: CYT-1 or CYT-2. CYT-1 nuclear translocation is critical for the expression of genes that are involved in the metabolic adaptations underlying Th1 activity.
Because CD46-CYT-1 lacks direct DNA-binding domains, we hypothesized that CYT-1 interacts with transcription factor (TF) activator and/or repressor complexes to control gene expression. ChIP-seq analyses of human CD4+ T cells using anti-CYT-1 antibody revealed 327 genes as direct CD46-CYT-1 targets and five conserved TF-binding motifs allowing us to define CYT-1-interacting TFs in T cells. Interestingly, pathway analysis of CYT-1-regulated genes identified broad nucleosome regulation as top ‘CYT-1 activity’. Indeed, we confirmed that CYT-1 directly regulates the expression and post-translational modification of core histones including H3 and H4 at lysine (4, 8, 9, 12, 20 and 27) in a time-dependent manner. Such CD46-driven nucleosome regulation was aberrant in T cells from CD46-deficient patients, explaining now mechanistically their inability to mount Th1 responses.
These data define a novel role for CD46 in chromatin packaging and support our notion that intracellular/autocrine complement regulates basic cell-physiological processes.