bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atrophied thymus produces altered repertoire of tTregs with potential to break the balance of peripheral tolerance
Authors: Thomas Rachel Ruth , Oh Jiyoung , Wang Weikan , Su Dongming 
Published: January 2023

Abstract
We have previously shown that in the age-related atrophied thymus, there is an increased ratio of thymic T regulatory (tTreg) cells to thymic T conventional (tTcon) cells, suggesting that the aged thymus has an enhanced tTreg generation. It is also known that in the periphery of aged mice and humans, there is an accumulation of peripheral Tregs. We raise the following question: why is the increased Treg population unable to suppress self-reactivity in the elderly? We utilized a sub-lethally irradiated chimeric mouse model in which OT-II TCR transgenic bone-marrow cells were transplanted into RIP-mOVA host mice. Therefore, OVA serves as a mock self-antigen, and because this transgene is driven by the rat insulin promotor, the pancreas of these mice expresses OVA. Further, the mOVA mice also carry a FoxN1-floxed gene, which can be conditionally knocked-out via CreERT transgene activation by injection(s) with tamoxifen to induce thymic atrophy. We observed that chimera mice with induced thymic atrophy show total Tregs (termed pan-Tregs) were increased but OT-II specific Tregs were slightly decreased in the spleen. Additionally, there is a dramatic decrease in the OTII-specific Tregs found in the pancreas, and pancreatic atrophy was observed in these mice compared to those with normal thymus. Our initial results suggest that thymic atrophy leads to a biased tTreg generation that manifests in decreased selftissue specific-Tregs. Therefore, although pan-Tregs may accumulate and be enhanced with age, tissue-specific peripheral tolerance may be poised to fail.
Mechanisms of maintenance of protection from persistent malaria infection by CD4 effector and effector memory T cells
Authors: Stephens Robin , Ibitokou Samad , Opata Michael M. 
Published: January 2023

Abstract
Generation of CD4 effector memory T cells (Tem) is associated with persistent infections. However, two counterintuitive features we identified obscure any mechanism for the predominance of Tem in chronic infection: that Tem differentiation begins very early in infection, and that Tem do not require persistent infection to survive. Within the first five days of Plasmodium chabaudi infection, the relative proportions of MPEC to SLEC (CD127− CD62Llo) are determined, and predict the ratio of Tcm to Tem. Furthermore, Tem survive as well as Tcm, and better than SLEC, in uninfected recipients. In addition, we determined that Tem are derived from the same memory precursor effector T cells (MPEC, CD127− CD62Lhi) as central memory T cells (Tcm). We have now identified three mechanisms promoting Tem numbers in chronic infection: 1) Tcm can be programmed by chronic infection to produce Tem, even after infection is over low-level, 2) persistent infection promotes turnover of Tem, and 3) some SLEC can also survive to generate Tem. These findings support the feasibility of generating protective Tem by vaccination. Another caveat to generating protection to chronic infection by vaccination, is that protection from disease can be improved by ongoing infection, suggesting a role for SLEC. Therefore, we tested both SLEC and Tmem subsets for contributions to protection, and found that SLEC protect best. Also, decay of SLEC coincides with declining protection as chronic infection is cleared. Nevertheless, one subset of Tem (CD127hiCD62LloCD27−) reduces parasitemia and pathology, and maintains Ifng expression in chronic infection. These findings provide important insight into mechanisms of development and maintenance of immunity to chronic infection.
Infiltrating CCR2+ Monocytes Drive Lethal Immunopathology during Cryptococcal Meningoencephalitis
Authors: Xu Jintao , Neal Lori , Ivey Mike , Lopez Rafael , Segal Benjamin , Osterholzer John J. , Williamson Peter R. , Olszewski Michal A. 
Published: January 2023

Abstract
Cryptococcal meningoencephalitis (CM) is a major cause of CNS-related mortality worldwide. While immunosuppression can lead to cryptococcal infection, immune responses are recently also reported to promote CNS injury during CM. The role of monocytes in both anti-cryptococcal protection and the CNS pathology during CM remains unknown, but CCL2 level in CNS are linked to mortality risk in HIV-associated CM.
To study the role of CCR2-axis recruited monocytes and monocyte derived cells (MDC) we evaluated outcomes of CM in WT versus CCR2-deficient mice. Fungal burdens, behavioral scores, pathology, immune parameters and mouse survival were compared. WT mice developed symptomatic disease and neurological deterioration from 3 weeks with 100% mortality by wk 5, despite a reduction in fungal burdens from wk 3 to wk 5. CCL2 production and MDC accumulation peaked at week 3, corresponding to onsets of symptoms and mouse mortality. Infiltrating MDC showed classical activation phenotypes (high level of iNOS/CD80 and low level of Arg1/CD206). In contrast, CCR2-deficient mice displayed a marked reduction in MDC recruitment relative to WT mice after infection. T cell inflammatory responses were diminished and switched from a Th1 response to mixed Th1/Th2/Th17 responses in CCR2 deficient mice. Furthermore, MDC activation shifted from M1 towards M2-type. These results show that CCR2-axis recruited MDC contributed to exuberant and detrimental Th1 inflammation. Survival of CCR2-deficient mice significantly improved despite impaired fugal clearance relative to WT mice. Taken together, we conclude that CCR2+ monocyte/MDC, while important for fungal clearance in CNS, are also critical mediators of inflammatory damage in CM.
Novel epitope derived from Plasmodium berghei liver-stage antigen induces a subset of protective CD8 T cells against sporozoite challenge
Authors: Pichugin Alexander V. , Zarling Stasya , Perazzo Leah , Duffy Patrick E. , Ploegh Hidde L. , Krzych Urszula 
Published: January 2023

Abstract
CD8 T cells specific for Plasmodium liver stage antigens (LS Ags) are considered key effectors in protective immunity induced by immunization with radiation-attenuated sporozoites (RAS). Sporozoite (spz)-stage epitopes that induce protective CD8 T cells have previously been identified, however, fine specificities of LS Ags-induced protective CD8 T cells remain unknown. Using transcriptome data based on LS forms of Plasmodium falciparum parasites, we identified several orthologue Plasmodium berghei (Pb) LS Ags that, as plasmid DNA vaccines delivered by Gene Gun immunization, significantly reduce liver parasite burden (LPB). Using algorithms that predict binding of peptides to H-2b alleles, we designed ~600 8–9 mer peptides derived from protective Pb LS Ags and screened them utilizing caged MHC class I-tetramer technology. Spleen cells from C57Bl/6 mice immunized thrice with Pb RAS and challenged with infectious spz were tested for binding to the conditional tetramers. We identified an H-2Kb-restricted 9-mer peptide, Kb-17, derived from the novel protective Pb LS Ag, MIF4G-like protein, that formed MHC class I-tetramer specifically binding CD8 T cells; the Kb-17 peptide also recalled IFN-γ responses in splenocytes and liver mononuclear cells at different time points after RAS immunization/challenge. The Kb-17 epitope, delivered as a minigene expressed in adenovirus 5, expanded Kb-17 specific CD8 T cells expressing effector memory phenotype and significantly reduced Pb LPB after infectious spz challenge. Identification of protective MHC class I-restricted epitopes on LS Ags as well as establishing a role for LS Ags-specific CD8 T cells in protection are crucial elements for vaccine development against malaria.
Requirement of CXCL11 chemokine production for induction of protection against pulmonary cryptococcosis
Authors: Castro-Lopez Natalia , Campuzano Althea , Hole Camaron , Leopold Wager Chrissy M. , Wozniak Karen , Wormley Floyd L. 
Published: January 2023

Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen that causes cryptococcal pneumonia in immunocompromised and immunocompetent individuals. We previously have shown that mice given an experimental pulmonary infection with a genetically modified strain of H99 that produces murine IFN-γ, H99γ, are able to completely resolve the pulmonary infection via the upregulation of the IFN-γ/STAT1 signaling pathway. Activation of STAT1 signaling leads to the production of CXCL9, CXCL10 and CXCL11 chemokines. These chemokines each serve as ligands for the CXCR3 receptor that is present on host immune cells including T cells, NK cells, dendritic cells (DCs) and plasmacytoid DCs and facilitate their chemotaxis to the site of infection. C57BL/6 (B6) mice produce a non-functional CXCL11 protein. Our studies show that B6 mice infected with C. neoformans strain H99γ have a 40% survival, compared to 100% survival in BALB/c mice and an 80% survival of F1 generation mice (first generation of BALB/c × B6) at day 60-post inoculation. After 60 days post-inoculation F1 mice infected with H99γ had a significant decrease in fungal burden compared to B6 mice. We also demonstrated that B6 mice do not produce CXCL11, as expected, at day 7 and 14 post-inoculation whereas F1 mice show a significant increase in the production of CXCL11 compared to B6 mice. Lastly, treatment of B6 mice given a pulmonary C. neoformans infection with recombinant CXCL11 resulted in a significant decrease in pulmonary fungal burden compared to untreated B6 mice infected with C. neoformans. These data suggest that activation of the STAT1-mediated signaling pathway and CXCL11 chemokine production is necessary for optimal protection against pulmonary C. neoformans infection.
Pathologic inflammation and neuronal damage during murine neurocysticercosis associates with increased expression of IL-1β
Authors: Cardona Astrid E. , Vanegas Difernando , Church Kaira , Mishra Pramod , Mares Chris , Cardona Sandra M. 
Published: January 2023

Abstract
Neurocysticercosis (NCC) is the leading cause of acquired epilepsy worldwide caused by Taenia solium larvae. Disease progression involves an initial asymptomatic phase followed by a symptomatic period, in which dying organisms induce inflammation and symptoms such as seizures, intracranial hypertension, or cognitive decline. A mixed Th1/Th2 response develops in the brain, contrasting the canonical Th2 pathway associated with peripheral helminthic infections. We found that disease progression was more severe in BALB/c mice, correlating with increased parasite burdens and enhanced eosinophil and macrophage infiltration, although comparable numbers of T cells were detected. Moreover, elevated IL-1β levels were significantly elevated in BALB/c mice. Notably, Mrc1-deficient mice which exhibited a more resistant phenotype with decreased mortality and morbidity displayed low IL-1β expression. Therefore, we hypothesize that early up regulation of IL-1β in response to antigen recognition by macrophages plays a key role in damage to the nervous tissue. Comparison of glial and neuronal distribution in naïve and infected wild type C57BL6 and Balb/c mice, and also in strains with defective trafficking of eosinophils to the CNS, revealed that expression of IL-1β was detected early during infection and dramatically increased by 2 wks, colocalizing to macrophages and astrocytes. Notably, calbindin+ neurons were also significantly reduced in cerebellar regions where severe pockets of inflammatory cells are detected. Thus, our results suggest that IL-1β is a central proinflammatory mediator with neurotoxic potential during NCC infection.
IL-4 signaling is required for optimal Th1 responses during Leishmania major infection
Authors: Gurung Prajwal , Poudel Barun 
Published: January 2023

Abstract
Leishmania spp. is a global health problem that affects more than 2 million people every year with 300 million people at risk worldwide. It is well established that a dominant Th1 response (IFN-gamma, a hallmark Th1 cytokine) provides resistance, while a dominant Th2 response (IL-4, a hallmark Th2 cytokine) confers susceptibility during Leishmania spp. infections. Given the important role of IL-4 during Leishmania major infections, we used IL-4 neutralizing antibody to study and investigate the cellular and molecular events regulated by IL-4 signaling. As previously published, neutralization of IL-4 in Leishmania major-infected BALB/c mice (a Leishmania susceptible strain) provided protection when compared to control Leishmania major-infected BALB/c mice. Interestingly, despite the protection, IFN-gamma production by T cells was dramatically reduced. This demonstrates two important and previously unknown points-1) the protection against Leishmania major does not depend on the amount of IFN-gamma, but rather on the amount of IL-4, and 2) IL-4 is required for optimal production of IFN-gamma by T cells. In conclusion, our studies break the pre-existing dogma of resistance/susceptibility to Leishmania spp. infections and open new research grounds to investigate the unsuspecting role of IL-4 in controlling Th1 responses. A complete understanding of these cellular and molecular crosstalk will hopefully uncover a much-needed novel therapeutic target to treat Leishmania major infections.
Clustering of CD8 T cells around malaria-infected hepatocytes is rapid and is driven by antigen-specific T cells
Authors: Ganusov Vitaly V. , Kelemen Reka , Rajakaruna Harshana , Cockburn Ian 
Published: January 2023

Abstract
Malaria, a disease caused by parasites of the Plasmodium genus, begins when Plasmodium-infected mosquitoes inject malaria sporozoites while searching for blood. Sporozoites migrate from the skin via blood to the liver, infect hepatocytes, and form liver stages. In mice, vaccine-induced CD8 T cells are capable of locating and eliminating all liver stages in 48 hours, thus preventing the blood-stage disease. We recently reported formation of clusters consisting of variable numbers of activated CD8 T cells around Plasmodium yoelii (Py)-infected hepatocytes. Using a combination of experimental data and mathematical models we now provide additional insights into mechanisms of formation of these clusters. First, we show that a model in which cluster formation is driven exclusively by T-cell-extrinsic factors, such as variability in “attractiveness” of different Py-infected cells, cannot explain distribution of cluster sizes in different experimental conditions. In contrast, the model in which cluster formation is driven by the positive feedback loop (i.e., larger clusters attract more T cells) can accurately explain the available data. Second, while both Py-specific CD8 T cells and T cells of irrelevant specificity (non-specific T cells) are attracted to the clusters, we found no evidence that non-specific T cells play a role in cluster formation. Third and finally, mathematical modeling suggested that formation of clusters occurs rapidly, within few hours after adoptive transfer of T cells, thus illustrating high efficiency of T cells in locating their targets in complex peripheral organs such as the liver. Our analysis thus clarifies details of the formation of clusters of antigen-specific CD8 T cells in the liver.
Microbiota metabolites short-chain fatty acid butyrate conditions intestinal epithelial cells to promote development of Treg cells and T cell IL-10 production
Authors: Xu Leiqi , Ma Chunyan , Huang Xiangsheng , Yang Wenjing , Chen Liang , Bilotta Anthony James , Yao Suxia , Cong Yingzi 
Published: January 2023

Abstract
Gut microbiota greatly impacts host immune response and intestinal homeostasis. However, the mechanisms are still largely unclear. Short chain fatty acids (SCFAs), the most abundant metabolites in intestines derived from gut bacterial fermentation of dietary fibers, either existing free in gut lumen or being absorbed into circulation, perform multiple functions in maintenance of intestinal epithelial integrity and immune homeostasis, and have been shown to directly induce Treg cells and ameliorate the colitis. However, the low concentration of SCFAs in bloodstream makes them hard to directly act on T cells in physiological condition. In this study, we investigated whether SCFAs regulate T cell development through interaction with intestinal epithelial cells (IECs), which are in constantly contact with high concentration of luminal SCFAs. We report here that treatment with SCFA butyrate induced IEC production of TGF-β in both primary IECs and cell line MSIE. We then cultured MSIE cells with or without butyrate for 24 and 48 hrs to generate condition media (CM). When added to T cell cultures under different polarization conditions, butyrate treated CM significantly enhanced the expression of Foxp3 under Treg conditions, and IL-10 production in Th1, Th17, and Treg cells. Furthermore, by using GPR43−/− IECs and the HDAC inhibitor, we found butyrate promotion of TGF-β production was partially mediated by its activity of HDAC inhibition but not through GPR43. Our study thus demonstrated that SCFA butyrate regulates host T cell responses through interaction with IECs. The trialogues of microbiota metabolites SCFAs, IECs, and T cells could play a crucial role in intestinal homeostasis.
Exposure to microbial antigens during early life is required for the establishment of tolerance to commensal &lt;a&gt;bacteria&lt;/a&gt;
Authors: Knoop Kathryn A. , Gustafsson Jenny K. , McDonald Keely G. , Hsieh Chyi-Song , Hogan Simon P. , Elson Charles O. , Tarr Phillip I. , Newberry Rodney D. 
Published: January 2023

Abstract
Current pediatric guidelines recommend breastfeeding and avoidance of oral antibiotics in the first years of life to reduce the risk of development of allergies. Additionally, animal models have shown exposure to the microbiota prior to weaning is necessary for the prevention of asthma or inflammatory diseases later in life. These studies suggest exposure to commensal microbes prior to weaning supports the development of tolerogenic responses in the intestinal tract. This interval of life coincides with the development of regulatory T cells in the colon which can suppress inflammatory responses. We have recently described a critical window for the development of tolerance in mice and found exposure to microbial antigens between 10 and 21 days of life occurred via the colon and induced long lived antigen specific FoxP3+ regulatory T cell responses. This window of tolerance is defined and regulated by ligands found in breastmilk and in the microbial milieu, and exposure to the microbial antigens required goblet cell associated antigen passages. Regulatory T cells developing during early life were required to restrain inflammatory responses against commensals later in life in a model of colitis. Additionally, exposure to commensal antigens via the colon after day of life 21 resulted in robust antigen-specific T effector responses and exacerbated inflammation in a model of colitis, exhibiting the critical nature of regulating this window of tolerance. Thus, exposure to microbial antigens early in life is an imperative element to the development of tolerance, and is highly regulated to prevent inflammation against the commensal microbiota.
IL-4 signaling regulates the IL-9 producing mast cells (MMC9) gene expression and function in food-induced anaphylaxis in mice
Authors: Tomar Sunil , Ganesan Varsha , Zeng Chang , Waggoner Lisa , Smith Andrew , Shik Dana , Wang Yui-Hsi , Hogan Simon 
Published: January 2023

Abstract
We have recently described an IL-9 producing mucosal mast cell population (MMC9s) that drives intestinal mastocytosis and food-induced anaphylaxis. The cytokine signaling pathways involved in the regulation of MMC9 function in food allergic reactions are currently not well understood. Employing a murine model of food-induced anaphylaxis and WT, gain-of-function Il4RaF709mice, and Il4Rα−/− mice we revealed an important role for IL-4 signaling in the enhancement of MMC9 frequency and this positively correlated with elevated serum levels of MCPT-1, CD4+TH2 cells, intestinal mastocytosis and increased susceptibility to food-induced anaphylaxis. Employing an adoptive transfer model of food allergy, we show direct IL-4 signaling is required for increased levels of MMC9 and development of food-induced anaphylaxis. RNA-seq analysis of purified WT, Il4RaF709and Il4Rα−/−MMC9s identified that IL-4-signaling pathway differentially regulates 238 genes that were identified to be associated with inflammatory responses and cytokine signaling processes by GO network analyses. Functional analysis revealed that IL-4 upregulates IL-9 and not IL-13 production in MMC9s. These results suggest that IL-4 signaling directly regulates MMC9 gene expression and function and onset of food-induced anaphylaxis. These studies suggest that targeting MMC9s through IL-4 signaling blockade maybe therapeutically beneficial for prevention and treatment of food allergy.
Dietary Early Glycation Products Protect Type 1 Diabetic Mice against Hyperglycemia through Altering Immune Homeostasis
Authors: Chen Yingjia , Guo Tai L. 
Published: January 2023

Abstract
Early glycation products (EGPs) are proteins modified with reducing sugar moieties. They are generated in the first step of Maillard reaction/glycation, and are precursors for the advanced glycation end-products (AGEs). This modification enhances the physiochemical properties of proteins (e.g. solubility), and has been proposed as a strategy to improve food protein qualities. However, the health effects of EGPs are rarely known. Our previous studies suggested that EGPs are anti-inflammatory. In contrast, AGEs are pro-inflammatory, and tightly associated with aging and hyperglycemia. It was hypothesized that EGPs were protective for type 1 diabetes (T1D) through modulating the immune homeostasis.
Food-borne EGPs were produced from a whey protein isolate-glucose model system. Six-week-old nondiabetic non-obese diabetic (NOD) mice were dosed with water, non-reacted samples (NR) and EGPs up for 8 wks. Body weight and blood glucose levels (BGLs) were measured weekly; diabetic incidence (BGLs &gt; 200 mg/dL) was recorded; glucose tolerance test and insulin tolerance test were conducted monthly; sera were separated; and spleen and thymus were harvested for flow cytometry analysis of the immune cell populations. The results showed that EGP-treated NOD mice exhibited significantly lower BGLs, delayed diabetes onset, less responsive to glucose challenge, and more sensitive to insulin challenge than water and NR-treated mice. Moreover, the diabetic NOD females displayed lower or even normal BGLs after EGP treatment. The flow cytometric data showed that EGP-treated mice had a significantly higher CD4/CD8 ratio than NR-treated mice. In conclusion, EGPs protected T1D mice against hyperglycemia through altering immune balance.