bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of new T Cell Epitopes in the mold aeroallergen Aspergillus fumigatus
Authors: Sternberg Luise , Seumois Gregory , Paul Sinu , Sidney John , Schulten Véronique MJ , Sette Alessandro , Vijayanand Pandurangan , Peters Bjoern 
Published: January 2023

Abstract
Exposure and sensitization to mold is frequently associated with severe asthma that does not respond to medication. The objective of our study is to identify a comprehensive set of T cell epitopes from the mold aeroallergen Aspergillus fumigatus (Asp), which will enable the isolation and study of T cells associated with severe asthma. To date, T cell epitopes have only been identified for three Asp allergens, all of which were originally identified based on their recognition by IgE antibodies. To derive a more comprehensive picture of T cell antigen recognition in Asp, we applied our validated 2D-gel immunoproteomics methods, and probed for IgE/IgG reactivity of Asp allergic patient plasma to proteins from two Aspergillus extracts. We also mined the literature for previously studied Asp allergens and antigens. From the proteins thus identified, we generated peptides and assessed them for HLA binding bioinformatically. This resulted in the identification of a total of 2,769 predicted HLA binding peptides. In order to identify which of these peptides can be recognized by T cells, we stimulated PBMCs of Asp-reactive donors with allergen extracts and screened for cytokine production in response to these peptides. The most reactive peptides were all from newly identified antigens, but also confirmed previously identified allergens Asp f 15 and Asp f 17 as sources of broadly reactive T cell epitopes. Thus, our work identifies a comprehensive picture of T cell antigens contained in Asp and commonly recognized T cell epitopes within them. This provides a tool for future studies of the immunopathology associated with mold allergy and asthma.
Functional impact of a cellular Long non-coding RNA on CCR5 expression and HIV infection
Authors: Kulkarni Smita , Lied Alexandra , Kulkarni viraj , singh sukhvinder , Rucevic Marijana , Martin Maureen P. , Chawdhury Fatema , Le Gall Sylvie , Yu Xu , Carrington Mary 
Published: January 2023

Abstract
An intergenic single nucleotide polymorphism (rs1015164 A/G) showed genome-wide significant association with HIV outcomes in previously published meta-analyses. We found that rs1015164 marks expression levels of an antisense long non-coding RNA, which we termed CCR5AS. CCR5AS interferes with the interaction between an RNA binding protein, RALY and the untranslated region of CCR5, and thus enhances CCR5 expression. Inhibition of CCR5AS decreased CCR5 mRNA as well as surface expression levels and reduced in vitro infection of CCR5-dependent HIV. Our data reveal a previously unknown mechanism by which a variation in a long non-coding RNA region affects HIV infection.
Chronic HCV infection, HCV/HIV coinfection and older age are independently associated with naïve CD4+CD31+ lymphopenia
Authors: Auma Ann , Kowal Corinne , Zebrowski Elizabeth , Damjanovska Sofi , Shive Carey , Osborne Melissa , Kalayjian Robert , Anthony Donald D 
Published: January 2023

Abstract

Background
Chronic Hepatitis C virus (HCV), HCV/HIV and aging are known to predispose to impaired immunity to vaccines, new infections and cancers. Naïve CD4+CD31+ lymphopenia is exhibited in all three conditions, and may be one contributor to impaired immunity. Whether age and chronic HCV or HCV/HIV infection status independently impact naïve CD4+CD31+ lymphopenia in older chronic infected individuals has not been described.

Methods
We enumerated naïve CD4+ and CD4+CD31+ absolute counts in chronic HCV (n=28) and ART controlled HCV/HIV (n=13) participants spanning a broad age range (HCV 27–87, HCV/HIV 27–70), and age distribution-matched uninfected controls (n=18, age 24–88) by flow cytometry. Kruskal-Wallis test (by SPSS) was used to compare variables across groups, and Spearmans rho test was used to evaluate correlations within individual groups.

Results
Naive CD4+ and CD4+CD31+ counts differed across groups (HCV, HCV/HIV and control groups, p=0.01 and p=0.03), while age did not differ across groups. Lower naive CD4+ and CD4+CD31+ counts were observed in the HCV infected participants compared to the controls (p=0.007 and p=0.01). Within the HCV group age negatively correlated with the naive CD4+ and CD4+CD31+ counts (r= −0.51 p=0.006, and r= −0.64 p&lt;0.001).

Conclusions
Both the state of infection (HCV or ART controlled HCV/HIV) and age independently impact naive CD4+ and CD4+CD31+ counts. Further studies are needed to understand how the mechanisms resulting in CD4+CD31+ lymphopenia during infection and ageing differ, and whether there is immune restoration following HCV DAA therapy.
Vδ1+ and Vδ2+ gamma delta T cells express different marker signatures and are distinctly linked to plasma markers of inflammation with ART-suppressed HIV infection and normal aging
Authors: Snyder-Cappione Jennifer E , Pihl Riley M , Olson Alex J , Lin Nina , Belkina Anna C 
Published: January 2023

Abstract
Our previous work implicates γδ T cells as an inflammatory driver in ART-suppressed HIV infection and suggests that this unique T cell population serves distinct roles in the ‘inflamm-aging’ that occurs with and without virally controlled HIV. In this study, we honed our previous findings to determine the precise γδ T cell subsets that are driving inflammation with age +/− HIV infection. We performed in depth immunophenotyping of circulating γδ T cells via multi-color flow cytometry and analysis of plasma markers of inflammation, coagulation, and intestinal permeability from subjects of our HIV and Aging cohort, which includes ART-suppressed HIV+ individuals and matched uninfected controls stratified by age into younger (≤35yo) and older (≥50yo) groups. We found discrete differences in the combinational expression the inhibitory receptors (IRs) TIGIT, PD-1, and CD160 between the Vδ1+ and the Vδ2+ γδ T cell subsets with HIV infection and healthy aging. Also, we found that specific IR signatures of Vδ1+ and Vδ2+ γδ T cells correlated with plasma inflammatory markers; however, different connections between the plasma analytes were found for each of the two γδ T cell subsets. Taken together, these data indicate that Vδ1+ and Vδ2+ γδ T cells exist in distinct states and possess divergent roles in the ‘inflamm-aging’ found in aviremic HIV+ infection and with normal aging. Further investigation into the anatomical locations, ex vivo functions, and additional surface markers that define γδ T cell subsets may reveal novel therapeutic targets to abrogate the aberrant inflammation found with HIV infection, aging, and other inflammatory conditions.
Role of Mycobacterium tuberculosis expressing unique protein Rv000B in immune modulation of host cell machinery
Authors: Arora Simran Kaur , Alam Anwar , Ahmad Javeed , Naqvi Nilofer , Hasnain Seyed Ehtesham , Ehtesham Nasreen Zafar 
Published: January 2023

Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb.), an intracellular pathogen remains a major global health problem. M.tb., comprising more than 120 species has evolved by successive genomic reduction events. Comparative genomic and proteomic analysis of 13 Mycobacterium species classified into Strict pathogens (virulent), Opportunistic pathogens (Non-tuberculous Mycobacteria, NTM) and the Non-pathogenic bacteria revealed the presence of 25 unique protein. These 25 proteins share less than 20% homology with any other proteins of Mycobacteria species used in the study. Rv000B, one of the unique proteins is present in M.tb and M. bovis BCG only. The presence of Rv000B in M. tb and M.bovis BCG only points to its importance as “Signature proteins”, suggesting that Rv000B could be used for its diagnostic potential. Rv000B is a hypothetical protein and hence it will be interesting to study their functional role in the pathogenesis of M.tb. In-silico analysis of Rv000B revealed that this protein is highly disordered and unstable. Immunogenicity of Rv000B protein was evaluated by treating the splenocytes ex-vivo obtained from mice that were previously immunized with Rv000B protein. Our results showed that Rv000B is highly antigenic and elicited a pro-inflammatory immune response. High IgG reactivity of Rv000B is also seen in immunized mice and different categories of TB patients. Besides inducing Th1 responses, it also significantly induced apoptosis of macrophages. Therefore, these pro-host antigenic proteins are ideal candidates to produce recombinant BCG vaccine to enhances its vaccine potential.
Induction of T cell-independent hypermutated and protective IgG and IgA antibody responses by TLR4-BCR or TLR5-BCR co-engagement
Authors: Rivera Carlos Eduardo , Chupp Daniel , Yan Hui , John IM , Wang Jingwei , Sanchez Helia Nasrollahi , Wu Shuai , Taylor Julia , Zan Hong , Xu Zhenming , Casali Paolo 
Published: January 2023

Abstract
Somatic hypermutation (SHM) and class-switch DNA recombination (CSR) together with plasma cell and memory B cell differentiation are central to the maturation of the antibody response. Prompted by our demonstrations that CSR and plasma cell differentiation can be induced in vitro by co-engagement of TLR4 and BCR, we tested the hypothesis that co-engagement of a TLR and BCR can induce mature T cell-independent antibody responses in vivo. To this end, we injected Tcrβ−/−Tcrδ−/− mice, which are devoid of all T cells, with TLR4-dependent NP-LPS or TLR5-dependent Salmonella flagellin. These mice readily generated NP-specific IgG antibodies and class-switched B cells and plasma cells. The high-affinity NP-LPS-induced IgG response was accompanied by a high-frequency of V186.2 region DNA mutations in class-switched B cells and NP-specific memory B cells. The TLR4-dependence and T cell-independence of this class-switched, anti-NP response was emphasized by immunedeficient NSG mice grafted with purified B cells, and mimicked in Tcrβ−/−Tcrδ−/− mice injected with TLR5-dependent flagellin. These mice generated flagellin-specific IgG and IgA, which displayed strong bactericidal activity and protected mice against Salmonella challenge. Thus, co-engagement of TLR4-BCR or TLR5-BCR, respectively, can effectively induce a mature and protective T cell-independent antibody response, thereby providing the basis for new TLR/BCR co-engagement-based B cell-targeted vaccine strategies.
Dissecting the role of proinflammatory chemokine CCL3 in the selection of germinal center B cells and in secondary antibody responses
Authors: Grigorova Irina , Benet Zachary , Ke Fang 
Published: January 2023

Abstract
Expression of CCL3 and CCL4 chemokines is upregulated in B cells upon crosslinking of B cell receptors and in germinal center (GC) centrocytes. However, the role of these proinflammatory chemokines in B cell responses is still unclear. Single cell qPCR analysis suggests that only a small fraction of GC centrocytes upregulates expression of CCL3/4. While B cell-intrinsic production of CCL3 promotes B cell interactions and negative control by follicular regulatory T cells at the peak of GC response, at the later stages of GC response it promotes B cells selection. Consistent with that, secondary antibody responses in CCL3 knockout mice are reduced. Our findings suggest that CCL3 is involved into multifaceted regulation of GC responses. Analyses of the mechanisms promoting both the negative and positive regulation of GC B cells in CCL3-dependent fashion are underway. These studies should be important for dissecting the role of CCL3 in normal immune responses and in B cell-originated lymphomas, where CCL3/4 are often elevated.
T follicular regulatory cells (Tfr) reduce proliferation and downregulate induction of costimulatory molecules on human Tfh and B cells
Authors: Sayin Ismail , Smith Carson , Buggert Marcus , Betts Michael R , Canaday David H. 
Published: January 2023

Abstract
Recently defined specialized subset of Treg expressing CXCR5+PD1+FoxP3+ termed as T follicular regulatory (Tfr) cells regulates T follicular helper (Tfh) mediated B cell high-affinity and isotype-switched antibody production. To date, much of our understanding of the suppression mechanism of Tfr cells has been obtained from animal studies. The mechanism of Tfr regulation of humoral immunity in humans is still understudied. Here, we used cells from human mesenteric lymph nodes to study how Tfr affect Tfh and B cells and what specific Tfr-induced changes occur on Tfh and B cells in vitro. We report that Tfr suppress both Tfh and B cell function and proliferation in a dose dependent manner. We find that Tfr downregulate CD40, CD80/CD86 and CD38 on B cells and CD28, OX40, ICOS and CD38 on Tfh cells. We also show that blocking immune checkpoint receptors inhibits Tfr suppression of Tfh and B cells and partially restores the Tfh mediated B cell antibody production. These findings reveal that Tfr regulate activation of Tfh and B cells by downregulating key costimulatory receptors and ligands that help induce activation in both Tfh and B cells. These changes ultimately lead to decreased proliferation of both B cells and Tfh and reduced production of immunoglobulin by B cells.
This research was supported in part by NIH R01 and VA.
Metabolic reprogramming of human pro-inflammatory B cells in aging and obesity
Authors: Blomberg Bonnie , Diaz Alain , Romero Maria , Frasca Daniela 
Published: January 2023

Abstract
The subset of pro-inflammatory B cells, called late memory (LM), tissuelike or double negative (CD19+CD27-IgD-), accumulates in the blood of elderly individuals. Here we show that LM B cells do not proliferate and do not make antibodies to new antigens (influenza vaccine), but they spontaneously secrete antibodies with autoimmune reactivity, due to spontaneous expression of the T-bet transcription factor. These cells also increase in the blood of individuals with obesity and autoimmune diseases, but causative mechanisms and signaling pathways involved are known only in part. Here we compare frequencies and metabolic requirements of these cells in the blood of healthy individuals of different ages and in the blood and subcutaneous adipose tissue (SAT) of individuals with obesity. Results show a metabolic reprogramming of LM B cells in aging and obesity, with LM B cells from young individuals having minimal metabolic requirements, LM B cells from elderly and obese individuals use higher amounts of glucose, make autoimmune antibodies and have higher aerobic glycolysis to support their function. LM B cells from the SAT have the highest metabolic requirements as they have increased oxidative phosphorylation, aerobic glycolysis and fatty acid oxidation. This metabolic reprogramming of LM B cells occurs after activation of AMPK (5′-AMP activated kinase) and Sestrins, both able to mitigate stress and cell death. These results indicate that metabolic reprogramming maintains LM B cells alive and maintains their function (secretion of autoimmune antibodies).
The IL-12/STAT4 pathway associates with critical functions in neutrophils
Authors: Keeter William Coles , Moriarty Alina , Ma Kaiwen , Glenn Lindsey , Waseem Tayab , Lattanzio Frank , Edemobi Stefan , Nadler Jerry , Kaplan Mark H , Galkina Elena 
Published: January 2023

Abstract
Signal transducer and activator of transcription 4 (STAT4) becomes activated via phosphorylation by JAK/Tyk kinases in response to IL-12 and other cytokines, which results in downstream transcription of pro-inflammatory genes. Our preliminary data are the first to demonstrate that IL-12 induces phospho-STAT4 in neutrophils. STAT4, JAK2, and p38 MAPK, but not Tyk2, become rapidly phosphorylated in response to IL-12 treatment in a time dependent manner. Pharmacologic inhibition of JAK1/2, but not p38, resulted in a two-fold reduction in phospho-STAT4, confirming its role as a signalling intermediate during STAT4 activation. Although IL-12 does not induce ROS formation in the short term (&lt;3 hours), we were surprised to discover a 4-fold increase in ROS production in response to long term IL-12 treatment (14 hrs), compared to only 1.5-fold increase in STAT4-deficient neutrophils. Additionally, we observed a dramatic 15-fold decrease in in vitro migration of STAT4-deficient neutrophils towards the chemoattractant GM-CSF compared to wild-type. Preliminary in vivo studies have revealed deficient migration to the peritoneal cavity of STAT4-deficient mice following intraperitoneal injection of GM-CSF. Finally, we demonstrate that in vitro NET formation in response to PMA treatment is impaired 5-fold in STAT4-deficient neutrophils compared to wild-type. These findings highlight the novel IL-12/STAT4 pro-inflammatory signalling pathway in murine neutrophils. Our data suggest a major contributory role of STAT4 in mediating neutrophil functions that have been previously associated with the progression of atherosclerosis. Future in vivo studies will determine the neutrophil-specific role of STAT4 in atherosclerotic mice.
Dermal Fibroblasts Control Mast Cell reactivity to commensal bacteria
Authors: Chang Yu-Ling , Sriram Krishna , Wang Zhenping , Igawa Satomi , Wu Chia-Chi , Insel Paul , Di Nardo Anna 
Published: January 2023

Abstract

Background
Our data suggests, and current literature supports, that when mast cells (MCs) leave the blood and interact with dermal fibroblasts (DFs), they assume a bacterial tolerant phenotype in order to prevent unnecessary inflammation during the encounter with the beneficial commensal microbiome. We hypothesize that the mechanisms that induce the MC tolerant phenotype in human skin is due to dermal fibroblasts interactions.

Methods
We mimicked the “in vivo” setting by conditioning human cord blood MC (hMC) with human dermal fibroblast (hDF) and, then exposed them to commensal bacteria supernatant. Human MC transcriptome data from the RNA-seq FANTOM5 data collection on MCs freshly isolated from human skin (FANTOM5 study Motakis_et_al_2013) was used to investigate the innate immune phenotype of MCs in the skin. We determined the genes that make hDFs unique by comparing their gene expression profiles with lung and cardiac fibroblasts using RNA-seq analysis and challenged hMCs with the products of these genes.

Results
We have discovered that hDF conditioned with hMCs, show a decreased expression of interleukins upon commensal stimulation; specifically, multiple cytokines/chemokine such as pro-inflammatory cytokine GM-SCF, IL-8, MCP-1 and anti-inflammatory cytokines IL-10, IL-13 are down-regulated by at least 95% and these cytokines can be controlled by the product of hDF unique genes.

Conclusion
The human dermal MC reactivity is controlled by hDF’s unique genes that play an important role in regulating the hMC NF-Kb pathway.
Allo-specific NK cells differentially regulate T cell allo-immunity depending on prenatal education
Authors: Kang Hee Kap , Turner Lucas , Redden Catherine , Shaaban Aimen F 
Published: January 2023

Abstract
Allospecific NK cell hyporesponsiveness develops after in utero hematopoietic cellular transplantation (IUHCT) in mice who exhibit stable long-term engraftment. Conversely, allospecific NK cell responses are normal in mice that reject their graft. We hypothesized that these alternate NK cell responses also differentially influence T cell responses after IUHCT.
To challenge this hypothesis, we compared the helper or suppression potential of prenatally educated NK cells between prenatal recipients with stable engraftment (engrafter mice) and littermates that rejected their graft (rejecter mice) in a Balb/c --- &gt; a B6 model of IUHCT. Allospecific NK cells from engrafter, rejecter, or naïve mice were co-cultured with naïve responder T cells (B6) and irradiated allogeneic target cells (Balb/c) in an in vitro IFN-g assay. Intracellular production of IFN-g was measured by flow cytometry of the naïve responder T cells after 66 hrs of co-culture.
We found that responder T cells displayed increased IFN-gamma production when co-cultured with allospecific NK cells from rejecter mice compared to co-culture with allospecific NK cells from naive control mice. Conversely responder T cells displayed decreased IFN-g production when co-cultured with allospecific NK cells from engrafter mice compared to co-culture with NK cells from naïve control mice.
From these results, we conclude that allospecific NK cells can influence the allospecific response of T cells in vitro depending on the context of their prenatal education. Further studies are needed to determine if similar mechanisms support engraftment or rejection in vivo.
PD-1 signaling impacts T cell function during the early phase of infection with Toxoplasma gondii
Authors: Perry Joseph Allan , Delong Jonathan , Clark Joseph , Park Jeongho , Gullicksrud Jodi , Shallberg Lindsey , Konradt Christoph , Christian David , Hunter Christopher 
Published: January 2023

Abstract
Long term resistance to T. gondii is mediated via T cell production of IFN-γ, but during chronic infection CD8+ T cells show signs of reduced capacity to secrete IFN-γ associated with increased expression of multiple inhibitory receptors. Blockade of the inhibitory receptor ligand PD-L1 during the chronic phase of infection has been reported to increase the functionality of CD8+ T cell responses and result in reduced parasite burden. However, the impact of PD-1 signaling on the immune response to T. gondii during the early phase of infection is unknown. PD-L1 blockade during the acute phase of toxoplasmosis resulted in an increased proportion of activated CD8+ T cells (CD69+, LFA-1hi) accompanied by an increased proportion of polyfunctional CD8+ T cells (IFN-γ+, Granzyme B+). This effect did not result in increased immune pathology or reduce parasite burden. Unexpectedly, this intervention resulted in a significant increase in the expression of inhibitory receptors such as PD-1, TIM3, and CTLA-4 on the long-lived T-intermediate (Tint, CXCR3+/KLRG1+) CD8+ T cell population, while increasing the proportion of terminally differentiated T cells in specific sites of infection. These datasets suggest PD-1 signaling in the early phase of T. gondii infection constrains CD8+ T cell effector differentiation and may act to preserve pathogen specific Tint subsets that are needed for long term resistance to this persistent infection.
PGAM1 hypomethylation drives aerobic glycolysis in CD4 T cells to facilitate the host defense against tuberculosis
Authors: Chen Xinchun , Zhu JiaLou , Zhu Chuanzhi , Gao Fei , Cai Yi 
Published: January 2023

Abstract

Background
DNA methylation is important epigenetic mechanism that mediates cellular development and function, but whether DNA methylation is involved in regulating CD4 T cells in the context of tuberculosis (TB) is unclear.

Results
We used oxidative bisulfite sequencing to measure global DNA methylation levels in isolated CD4 T cells from patients with tuberculous pleuritis (TP), latent TB infection (LTBI) and healthy controls (HC). Compared to peripheral blood mononuclear cells (PBMCs), CD4 T cells from pleural fluid mononuclear cells (PFMCs) showed a significant different global DNA methylation profile, with much lower 5-methylcytosine levels in PFMC. A signature of 376 differentially methylated regions could discriminate between TP PBMC and PFMC T cells, including hypermethylated LAPTM5, FAM134B and FOXP1, and hypomethylated CCL5, TNF and AIM2 in PFMCs. KEGG pathway analysis showed that numerous metabolic pathways, especially ‘Carbon metabolism’, were highly enriched among the differentially methylated genes with lower methylation levels in TP PFMCs. Hypomethylation of the glycolytic enzyme PGAM1 promoted gene expression and increased aerobic glycolysis in CD4 T cells to permit CD4 T-cell proliferation and effector function.

Conclusions
Diminished DNA methylation levels —especially in genes involved in metabolism —are an important CD4 T-cell signature at the site of infection in TB. DNA hypomethylation of PGAM1is critical mechanism in regulating the CD4 T-cell immune response by enhancing aerobic glycolysis. These findings provide novel insights into the epigenetic regulation of CD4 T-cell responses and identify potential targets for immunotherapy in TB.