bluuebunny/crossref_metadata_2025_split huggingface dataset:
The class II peptide editor, H2-M, affects the development and function of B-1 cells
Authors: Ghosh Debopam , He Xiao , O’Mara Mary E , Kantor Aaron B , Sengupta Deepanwita , Yang Yang , Eisenlohr Laurence C , Jensen Peter E , Herzenberg Leonore A , Mellins Elizabeth D 
Published: January 2023

Abstract
B-1 cells are known for their innate, polyreactive BCR repertoire, and proficiency at polarizing T cells towards inflammatory effector T cells, a critical component in host defense and autoimmunity. B-1 cells are antigen presenting cells (APCs) and express MHCII proteins to bind and display self and foreign peptides to CD4 T cells. H2-M edits peptide-MHCII complexes to ensure display of stably bound peptides by APCs. Absence of H2-M has most widely been studied for its impact on T cell activation, but knowledge of how this protein affects the development and function of APCs is lacking. We found that absence of H2-M down-regulated the surface expression and altered the distribution of MHCII molecules in B cells across lymphoid organs. Importantly, in H2-M KO mice, compared to the wild-type C57BL/6 (B6) mice, the frequency and abundance of B-1 cells, but not conventional B-2 cells was affected. Interestingly, the H2-M mediated effect on B-1 cell population was only evident in I-Ab expressing B6, not in Balb/c (I-Ad/I-Ed), indicating an MHCII haplotype dependent effect. Decrease in B-1 cell number was evident in both immature and mature B-1 cells, further indicating an H2-M mediated developmental defect of B-1 cells. In H2-M KO mice, B-1 cells display a significantly lower self-renewal capacity and higher rate of apoptosis compared to WT B6. Despite a lower total B-1 cell number, the frequency of B-1 cells specific for predominant self-antigens (like – phosphatidylcholine) is increased in H2-M KO mice, indicating skewing of B-1 BCR repertoire in absence of H2-M. Collectively, these data identify a novel impact of H2-M/MHCII interaction that regulates the development of B-1 cells and influences the selection of mature B-1 cell clones in the periphery.
IRF4 regulates the proliferative response during B cell differentiation in vivo
Authors: Patterson Dillon , Scharer Christopher , Mi Tian , Hicks Sakeenah L , Zhang Qiang , Boss Jeremy M 
Published: January 2023

Abstract
Cell division is an essential component of B cell differentiation to a plasma cell (PC). Division coupled changes in the expression of transcription factors that coordinate the PC program are known; however, little is known regarding the timing/extent of reprogramming by these factors as the cells are dividing in vivo. Furthermore, how/when these factors coordinate cell division during differentiation has remained unexplored. To address this, we assessed the cell division kinetics of wild-type (WT) B cells responding to LPS in vivo. Interestingly, we found that WT B cells must undergo 8 divisions before differentiating into PCs. Computational modeling of division rates defined a proliferative burst between 48 and 60 hours after LPS injection that is characterized by a rapid increase in the rate of cell division. In contrast, Interferon Regulatory Factor 4-deficient (IRF4−/−) B cells divided but stalled at divisions 2–6, failing to undergo the proliferative burst. To assess the timing/scope of IRF4-dependent reprogramming, WT and IRF4−/− responding B cells at divisions 0, 1, and 3–6 were sorted for ATAC- and RNA-seq. RNA-seq data revealed hundreds of differentially expressed genes (DEGs) when IRF4 was deleted, a subset of which included Myc target genes. ATAC-seq data also exposed hundreds of differentially accessible regions (DARs), the majority of which contained a known IRF4 binding motif and mapped to a corresponding DEG. Interestingly, IRF4−/− B cells progressively became more divergent as they divided when compared to WT B cells in the same division. Together, these data create a road map defining the role of IRF4 throughout B cell differentiation and reveal a critical role for IRF4 in maintaining the proliferative response.
Hypoxia and TGF-β1 induce tissue resident memory phenotype cells from human peripheral blood T-cells in vitro
Authors: Hasan Farah , Shaw Rebecca , Wang Junmei , Yee Cassian 
Published: January 2023

Abstract
Tissue resident memory cells (TRM) are a recently identified subset of memory T-cells important in frontline defense against viral diseases and recent reports suggest T-cells with this phenotype are important in anti-tumor immunity. However, relatively little is known regarding TRM differentiation and endogenous TRM are notoriously difficult to isolate, impeding their study in basic research and downstream applications. Thus a means to generate TRM in vitro would be desirable. It is known that TGF-β is critical in establishing TRM populations and attempts to identify other factors that can induce differentiation to resident phenotype have focused on cytokines. Oxygen tension is another factor that distinguishes the circulation from peripheral tissues; thus we hypothesized that hypoxia may contribute to a TGF-β1-induced TRM phenotype in human CD8+ T-cells. We demonstrate that differentiation of human peripheral blood CD8+ T-cells in hypoxia and TGF-β1 in vitro led to the development of a TRM phenotype, characterized by a significant increase in CD69+CD103+ cells expressing CD49a, CD101, and PD-1 – hallmarks of human TRM. At the transcriptional level we observed upregulation of genes associated with TRM differentiation and downregulation of genes associated with memory cell recirculation. Hypoxia and TGF-β1 appear to synergize to induce a resident phenotype as their combination produced a significantly larger population of TRM phenotype cells than the additive effects of either condition alone. Our findings identify a previously unreported cue for TRM differentiation and enable a facile means of generating human TRM phenotype cells in vitro for basic studies and translational applications such as adoptive cellular therapies.
Identity of recirculating T cells i humans
Authors: Buggert Marcus , Nguyen Son , Darko Samuel , Ransier Amy , Douek Daniel , Björkström Niklas K. , Dori Yoav , Itkin Max G. , Betts Michael R 
Published: January 2023

Abstract
Memory T cells are widely considered to continually recirculate between tissues and blood via lymph to maintain immunosurveillance. While much effort has been dedicated to understand which memory T cells that are present in tissues, less is known about peripheral blood memory T cell subsets that recirculate through and egress from tissues during steady-state. Here we directly identify the tissue egressing (recirculating) immune system by sampling thoracic duct lymph (TDL), blood and peripheral tissues in humans and primates. We find that 70% of all immune cells egressing from tissues are T cells. Through transcriptional, functional, clonotypic, and epigenetic profiling, we find that cytolytic memory CD8+ T cell subsets are almost entirely confined to blood, while their phenotypic counterparts in TDL and many tissues represent non-cytolytic cells with higher regenerative capacity. Cytolytic T cells in blood possess a distinct clonotype distribution compared to TDL CCR7- T cells and are retained in blood after treatment with the tissue egress inhibitor fingolimod. We additionally find that HIV-specific CD8+ T cells can be readily found in TDL but again lack a cytolytic phenotype. We propose that cytolytic molecule expression is confined to a blood-resident memory T cell population in steady-state and that the intermediate differentiation status of HIV-specific CD8+ T cells is a fingerprint of their systemic recirculation capacity, rather than dysfunction, in humans.
Role of the Microbiota in Primary Lung Cancer Initiation and Progression
Authors: Rose uriel D , Vetizou Marie , Roy Soumen , Edwards Bathai , Peck Misty , Smith Loretta , Robles Ana , Harris Curtis , Difilippantonio Simone , Trinchieri Giorgio 
Published: January 2023

Abstract
Lung cancer is the leading cause of cancer-related death in men in 87 countries and in women in 26 countries. The commensal microbiota lives on the epithelial barriers of the host and is vital for the health of the organism. Specific microbial species have been described to affect neoplastic pathology both at the gastrointestinal tract level and systematically in organs that are not normally associated with the gut microbiota. Studies have revealed the importance of the gut microbiota in the efficacy of anti-cancer therapies (chemo and immunotherapy) However, the role of lung microbiome in lung cancer remains largely unknown. We aimed to study the role of the lung microbiota during lung carcinogenesis progression in the context of p53/K-ras mutation and its impact on the tumor microenvironment. To further analyze the impact of the lung microbiota on lung cancer initiation, P53-Kras mutant germ-free mice will be colonized by intranasal instillation with bacteria identified in human lungs samples from lung cancer patients such as Variovorax paradoxus (V.paradoxus) and Acidovorax temperans (A.temperans) and the tumor burden will be calculated. Our data indicates Germ-free mice instilled with V. paradoxus trended towards an increase tumor burden compared to respective controls while A. temperans -associated germ-free mice seems to delay tumor growth. Germ-free mice, at 18 and 24 weeks post-Ad-Cre virus instillation, tends to have an increased tumor burden than their SPF counterparts. Also, changes in immune infiltrate were observed after flow cytometric analysis with preliminary data showing a decrease in CD45 positives cells the cells in mice instilled with V. paradoxus as well as an increase in Monocytes and Macrophages populations.
Induction of a long non-coding RNA, lncRNA-Chr1:1226, by Cryptosporidium infection primes intestinal epithelial cells for IFN-γ-mediated host antimicrobial gene transcription
Authors: Chen Xian-Ming , Deng Silu , Gong Ai-Yu , Wang Yang , Zhang Xin-Tian , Li Min , Li Juan , Mathy Nicholas W 
Published: January 2023

Abstract
Cryptosporidium, a protozoan parasite that infects the intestinal epithelium and other mucosal surfaces in animals and humans, is an important opportunistic pathogen in AIDS patients and a common cause of diarrhea in young children in developing countries. Intestinal epithelial cellular defense is key to innate mucosal anti-Cryptosporidium defense but underlying molecular mechanisms are still obscure. Here, we identified several long non-coding RNAs (lncRNAs) that are predominantly expressed in intestinal epithelial cells. Several of such epithelial-enriched lncRNAs, such as lncRNA-Chr1:1226, were upregulated in cells following C. parvum infection. Induction of lncRNA-Chr1:1226 in infected intestinal epithelial cells was controlled by TLR4/NF-κB/Cdc42 signaling and epithelial specific transcription factor Eif3. Induction of lncRNA-Chr1:1226 promoted IFN-γ-mediated epithelial antimicrobial defense, through facilitating STAT1/SWI/SNF-associated chromatin remodeling to promote IFN-γ-mediated transcription of defense genes in intestinal epithelial cells. We observed that IFN-γ-mediated antimicrobial defense was suppressed in neonatal intestinal epithelium. Expression of PRDM1 in the neonatal intestinal epithelium might contribute to suppression of IFN-γ-mediated antimicrobial gene transcription. Furthermore, PRDM1 interacted with lncRNA-Chr1:1226 and PIAS1 to attenuate SWI/SNF-mediated antimicrobial transcription induced by IFN-γ in intestinal epithelium of neonates. Our data demonstrate that lncRNAs, particularly epithelial lncRNAs, may be key regulators in IFN-γ-mediated epithelial defense.
Infiltrated monocyte and T cell interaction drives immunopathology in the brain during cryptococcal meningoencephalitis
Authors: Xu Jintao , Ivey Mike , Koble Jessica , Lopez Rafael , Mechler Claire , Neal Lori , Williamson Peter , Segal Benjamin , Olszewski Michal A 
Published: January 2023

Abstract
Cryptococcal meningoencephalitis (CM) is a major cause of central nervous system (CNS)-linked mortality worldwide. High mortality frequently occurs despite antifungal drug treatment and pathogen elimination, and increasing evidence suggests over-exuberant host immune responses promote CM pathogenesis. Our goal was to dissect the role of two major groups of cells recruited to CNS (myeloid cell and T cell) and determine whether and how their crosstalk drives CM immunopathology.
To study this, we developed a murine model that reproduces major features of human CM. Using this model, we found mice mortality did not directly correlate with CNS fungal burden, but instead was synchronized with the accumulation of ultra-Th1 polarized CD4 T cells and CCR2+ monocytes (Mo). Recruitment of Mo into the CNS was impaired in CCR2−/− mice, and these mice survived significantly longer and displayed fewer neurological symptoms despite higher brain fungal burden compared to WT mice. Mechanistically, we found that 1) CCR2+ Mo contributed to CXCR3+IFNγhi CD4 T cell accumulation and their ultra-Th1 polarization through modulating CXCL9/CXCL10 production. 2) CXCR3 deletion resulted in diminished CD4 T cell recruitment, Th1 polarization and conferred markedly protection against CM mortality; 3) robust IFNγ production by CD4 T cells corresponded to massive iNOS expression in Mo, which propose excessive NO production potentially contributes to neuronal injury. Collectively, we showed CCR2+ Mo and CXCR3+ CD4 T cells interact to promote mutual recruitment and activation, causing profound CNS damage during CM. Regulation of Mo and T cell function may become therapeutic strategy to aid current anti-fungal drug treatment that is frequently ineffective.
Microbial Activation of B-cells by Pattern Recognition Receptors Contributes to the Proinflammatory and Profibrotic Milieu in Patients with Idiopathic Pulmonary Fibrosis
Authors: Ali Mohamed , Dasari Harika , Van Keulen Virginia , Egan Ashley , Peikert Tobias , Carmona Eva M 
Published: January 2023

Abstract
We hypothesize that B-lymphocytes are conducive to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a progressive and fatal interstitial lung disease. B-lymphocytes aggregate in the lungs of IPF patients to form tertiary lymphoid follicles. How these follicles are formed and their role in the pathogenesis of IPF is not known. Hence, we sought to characterize how the activation of B-lymphocytes from IPF patients may contribute to the disease.

Methods
IPF patients defined by ATS guidelines were identified and recruited under local IRB #14-004714. B-lymphocytes were then isolated by negative selection. Cytokines and immunoglobulins from plasma or B-lymphocyte supernatants were measured by ELISA and signaling pathways were elucidated from whole-cell lysates by immunoblotting. Our results show that B-lymphocyte aggregates are present within fibrotic areas of the lung of IPF patients and that activated B-lymphocytes induce fibroblast migration. This effect was abrogated by nintedanib inhibition of B-lymphocyte activation. Furthermore, microbial antigen (β-glucan and CpG) activation of B-lymphocytes through pattern recognition receptors (PRRs; TLR9 and Dectin-1) contributed to the proinflammatory and profibrotic milieu seen in IPF patients. Stimulation of TLR9 and Dectin-1 resulted in activation of mTOR-dependent and -independent pathways, respectively. Rapamycin decreased TLR9 signaling, but not Dectin-1 mediated pathways. Nintedanib abrogated B-cell activation, IgM production, and the profibrotic milieu by interfering with both the mTOR-dependent and -independent pathways. In conclusion, our findings implicate activated B-lymphocytes in IPF pathogenesis highlighting the role of PRRs in this disease.
Long Pentraxin 3 (PTX3) Regulates IL-17A Mediated Immunity to Primary and Secondary Leishmania major Infection
Authors: Gupta Gaurav , Jia Ping , Sharma Rohit , Zayats Romaniya , Shan Lianyu , Mou Zhirong , Murooka Thomas , Soussi-Gounni Abdelilah , de Oliveira Camila I , Uzonna Jude E 
Published: January 2023

Abstract
Resolution of cutaneous leishmaniasis (CL), caused by the protozoan parasite Leishmania (L) major, relies on the nature of the host immune response. The long pentraxin 3 (PTX3), a soluble pattern recognition molecule, is critical for wound healing by regulating tissue repair and also in innate and adaptive responses during infection and inflammation. Here, we show that PTX3 regulates disease pathogenesis and immunity to CL. PTX3 expression is increased in active skin lesions in patients and mice during CL, with higher levels being expressed in individuals with severe disease. PTX3−/− mice were highly resistant to primary and secondary L. major infection. Interestingly, the enhanced resistance of PTX3−/− mice to primary or secondary L. major infection was not associated with enhanced IFN-γ or decreased IL-10 response. Instead, L. major-infected PTX3−/− mice displayed strong IL-17 response and in vivo neutralization of IL-17A abolished their enhanced resistance. Naïve CD4+ T cells from PTX3−/− mice displayed increased differentiation into Th17 cells and this was associated with increased expression of Th17-specific transcription factors including RORγt, AhR and STAT3. Addition of recombinant PTX3 significantly inhibited the expression of Th17-specific transcription factors and the frequency of Th17 cells in Th17 polarizing cultures of PTX3−/− CD4+ T cells. Similarly, healed PTX3−/− mice had higher frequencies of effector memory CD4+ T cells that rapidly proliferate and differentiate into IL-17A-producing CD4+ T cells upon secondary challenge. Collectively, our results show that PTX3 contributes to pathogenesis of CL by negatively regulating protective Th17 and IL-17 responses.
Gamma Delta and Natural Killer cells in Splenocytes of Young mice Protect Immunocompromised mice from Death in Plasmodium chabaudi Infection
Authors: Richard Lyndsay B , Smith Margaret R. , Murrray Annie E , Opata Michael M 
Published: January 2023

Abstract
Immunity to malaria requires an elongated time to develop and understanding of the immune response to malaria, especially in children under five, is limited due to the lack of a reliable animal model to study the pathogenesis of the disease. By utilizing a newly developed young rodent model in our lab, we have observed that purified CD4+ T cells from 8-week adult mice proliferate faster than day 15 old young mice (pups) when stimulated in vitro. Surprisingly, we observed faster proliferation of splenocytes in the pups, when compared to the cells from adult mice. When transferred to immunocompromised RAGKO mice, both pup and adult cells protected from death. These data suggest that apart from CD4+ T cells, there is a faster responsive cell population in the pups that may promote protection against malaria infection in mice. To better understand this responsive cell population in young mice, we adoptively transferred splenocytes from both adults and pups into immunocompromised RAGKO mice and infected these cell recipients with P. chabaudi. We observed higher proportions and numbers of gamma delta (gd) T cells in the pup splenocyte recipients when compared to adult counterparts on day 8 post-infection. Interestingly, we observed lower proportions and numbers of natural killer (NK) cells in the adult cell recipients compared to pup recipients. However, there were significantly higher proportions, but not numbers of macrophages in the adult cell recipients. Taken together, our findings suggest that pup cells are enriched or promote an innate immune response comprising of gd and NK cells, while adult cells inhibit the expansion of these innate lymphocyte cells in malaria infection.
Pulmonary inflammation and Tie2/Angiopoietin mediated vascular dysregulation during lethal Orientia tsutsugamushi infection
Authors: Trent Brandon J , Liang Yuejin , Xing Yan , Esqueda Marisol , Yang Wei , Cho Nam-Hyuk , Kim Hong-Il , Kim Yeon-Sook , Shelite Thomas R , Cai Jiyang , Sung Jiaren , Bouyer Donald , Liu Peter , Soong Lynn 
Published: January 2023

Abstract
Orientia tsutsugamushi infection can cause acute lung injury and high mortality in humans; however, the underlying mechanisms are unclear. Here, we tested a hypothesis that dysregulated pulmonary inflammation and Tie2-mediated endothelial malfunction contribute to lung damage. Using a murine model of lethal O. tsutsugamushi infection, we demonstrated pathological characteristics of lung damage: 1) a significant increase of ICAM-1, VEGFR2, and angiopoietin-2 (Ang2) proteins in inflamed tissues and lung-derived endothelial cells (EC), 2) a progressive loss of endothelial quiescent and junction proteins (Ang1, VE-cadherin), and 3) a profound impairment of Tie2 receptor at the transcriptional and functional levels. In vitro infection of primary human EC cultures and serum Ang2 proteins in scrub typhus patients support our animal studies, implying endothelial dysfunction in severe scrub typhus. Evidence for neutrophil-mediated inflammation and tissue damage included in vitro infection and activation of neutrophils, lung accumulation of activated (CD63+)neutrophils, co-localization of lung bacteria with neutrophils, and co-localization of MPO+ neutrophils with Ang2+ ECs. At the onset of disease, pulmonary macrophages (MF) were polarized toward an M1-like phenotype, with limited detection of M2-like cells. Comparative studies of LPS- versus IL-4-primed MFs revealed extensive bacterial replication in M2-type MFs that preferentially expressed the IL-10 and SOCS1 genes. This is the first detailed investigation of lung cellular immune responses during acute O. tsutsugamushi infection and highlights inflammatory biomarkers future therapeutic research for the control of this neglected tropical disease.
Pre-existing SIV infection decreases cytokine responses by T cells in lung during the early stages of M. tuberculosis co-infection
Authors: Larson Erica C , Rodgers Mark A , Ellis Amy L , Ameel Cassaundra L , Baranowski Tonilynn M , Balgeman Alexis J , Maiello Pauline A , O’Connor Shelby L , Scanga Charles A 
Published: January 2023

Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death among HIV+ individuals. The precise mechanisms by which HIV impairs the immune response to subsequent Mtb infection are unknown. We previously established a model of co-infection in Mauritian cynomolgus macaques (MCM). We found SIV/Mtb co-infected MCM had rapidly progressive TB and reached humane endpoint by 12 weeks post-Mtb infection. We hypothesized that pre-existing SIV impacts T cell responses at the early stages of Mtb infection. We infected MCM with SIVmac239 intrarectally and 6 months later co-infected with a low dose of Mtb. SIV-naïve MCM were infected with Mtb alone as controls. Animals were monitored by clinical parameters, culturing bacilli in gastric and bronchoalveolar lavages, and serial 18F-FDG PET/CT imaging. Six weeks after Mtb infection, animals were necropsied and immune responses in the lung were measured by flow cytometry. The two groups exhibited similar TB disease at time of necropsy. Total bacterial burden was remarkably high in both SIV-naïve and SIV/Mtb groups, although co-infected animals tended to have more bacteria in lung tissue. At sites of Mtb infection, SIV/Mtb co-infected animals had fewer CD4+ T cells and significantly more CD8+ T cells. TNFα production by these CD4+ and CD8+ T cells was decreased. Taken together, pre-existing SIV decreases the quality of cytokine responses by T cell at sites of Mtb infection during the early stages of TB disease. This appears to be a critical time point at which the immunologic defect from pre-existing SIV infection begins to impact the arc of TB disease.