IU Indianapolis ScholarWorks :: Browsing by Author "Ulrich, Benjamin J."

Browsing by Author "Ulrich, Benjamin J."

Now showing 1 - 10 of 15

Allergic airway recall responses require IL-9 from resident memory CD4+ T cells
(American Association for the Advancement of Science, 2022) Ulrich, Benjamin J.; Kharwadkar, Rakshin; Chu, Michelle; Pajulas, Abigail; Muralidharan, Charanya; Koh, Byunghee; Fu, Yongyao; Gao, Hongyu; Hayes, Tristan A.; Zhou, Hong-Ming; Goplen, Nick P.; Nelson, Andrew S.; Liu, Yunlong; Linnemann, Amelia K.; Turner, Matthew J.; Licona-Limón, Paula; Flavell, Richard A.; Sun, Jie; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
Asthma is a chronic inflammatory lung disease with intermittent flares predominately mediated through memory T cells. Yet, the identity of long-term memory cells that mediate allergic recall responses is not well defined. In this report, using a mouse model of chronic allergen exposure followed by an allergen-free rest period, we characterized a subpopulation of CD4+ T cells that secreted IL-9 as an obligate effector cytokine. IL-9-secreting cells had a resident memory T cell phenotype, and blocking IL-9 during a recall challenge or deleting IL-9 from T cells significantly diminished airway inflammation and airway hyperreactivity. T cells secreted IL-9 in an allergen recall-specific manner, and secretion was amplified by IL-33. Using scRNA-seq and scATAC-seq, we defined the cellular identity of a distinct population of T cells with a proallergic cytokine pattern. Thus, in a recall model of allergic airway inflammation, IL-9 secretion from a multicytokine-producing CD4+ T cell population was required for an allergen recall response.
An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment
(American Association for the Advancement of Science, 2022) Fu, Yongyao; Wang, Jocelyn; Zhou, Baohua; Pajulas, Abigail; Gao, Hongyu; Ramdas, Baskar; Koh, Byunghee; Ulrich, Benjamin J.; Yang, Shuangshuang; Kapur, Reuben; Renauld, Jean-Christophe; Paczesny, Sophie; Liu, Yunlong; Tighe, Robert M.; Licona-Limón, Paula; Flavell, Richard A.; Takatsuka, Shogo; Kitamura, Daisuke; Tepper, Robert S.; Sun, Jie; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9-responsive cell repertoire is still not well defined. Here, we found that IL-9 mediates proallergic activities in the lungs by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c+ and CD11c- interstitial macrophage populations. Interstitial macrophages were required for IL-9-dependent allergic responses. Mechanistically, IL-9 affected the function of lung macrophages by inducing Arg1 activity. Compared with Arg1-deficient lung macrophages, Arg1-expressing macrophages expressed greater amounts of CCL5. Adoptive transfer of Arg1+ lung macrophages but not Arg1- lung macrophages promoted allergic inflammation that Il9r-/- mice were protected against. In parallel, the elevated expression of IL-9, IL-9R, Arg1, and CCL5 was correlated with disease in patients with asthma. Thus, our study uncovers an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation.
BATF-Interacting Proteins Dictate Specificity in Th Subset Activity
(American Association of Immunologists, 2020-10-01) Fu, Yongyao; Koh, Byunghee; Kuwahara, Makoto; Ulrich, Benjamin J.; Kharwadkar, Rakshin; Yamashita, Masakatsu; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
The basic leucine zipper (bZIP) transcription factor BATF is expressed in multiple Th subsets and cooperates with other factors to regulate gene transcription. BATF activates lineage-specific cytokines in Th subsets, activating IL-9 in Th9 cells and IL-17 in Th17 cells, but not IL-9 or IL-17 in the reciprocal subset. The mechanism for this restricted activity is unclear. In this report we define BATF binding partners that contribute to Th subset-specific functions. Although BATF and IRF4 are expressed in greater amounts in Th9 than Th17, increased expression of both factors is not sufficient to induce IL-9 in Th17 cells. BATF also requires heterodimer formation with Jun family members to bind DNA and induce gene expression. Using primary mouse T cell culture, we observed that JunB and c-Jun, but not JunD, promote IL-9 production in Th9 cells. Ectopic expression of BATF with either JunB or c-Jun generates modest but significant increases in IL-9 production in Th17 cells, suggesting that the low expression of Jun family members is one factor limiting the ability of BATF to induce IL-9 in Th17 cells. We further identified that Bach2 positively regulates IL-9 production by directly binding to the Il9 gene and by increasing transcription factor expression in Th9 cells. Strikingly, co-transduction of Bach2 and BATF significantly induces IL-9 production in both Th9 and Th17 cells. Taken together, our results reveal that JunB, c-Jun and Bach2 cooperate with BATF to
Bcl6 and Blimp1 reciprocally regulate ST2+ Treg-cell development in the context of allergic airway inflammation
(Elsevier, 2020) Koh, Byunghee; Ulrich, Benjamin J.; Nelson, Andrew S.; Panangipalli, Gayathri; Kharwadkar, Rakshin; Wu, Wenting; Xie, Markus M.; Fu, Yongyao; Turner, Matthew J.; Paczesny, Sophie; Janga, Sarath Chandra; Dent, Alexander L.; Kaplan, Mark H.; Pediatrics, School of Medicine
Background Bcl6 is required for the development of T follicular helper cells and T follicular regulatory (Tfr) cells that regulate germinal center responses. Bcl6 also affects the function of regulatory T (Treg) cells. Objective The goal of this study was to define the functions of Bcl6 in Treg cells, including Tfr cells, in the context of allergic airway inflammation. Methods We used a model of house dust mite sensitization to challenge wild-type, Bcl6fl/fl Foxp3-Cre, and Prdm1 (Blimp1)fl/fl Foxp3-Cre mice to study the reciprocal roles of Bcl6 and Blimp1 in allergic airway inflammation. Results In the house dust mite model, Tfr cells repress the production of IgE and Bcl6+ Treg cells suppress the generation of type 2 cytokine–producing cells in the lungs. In mice with Bcl6-deficient Treg cells, twice as many ST2+ (IL-33R+) Treg cells develop as are observed in wild-type mice. ST2+ Treg cells in the context of allergic airway inflammation are Blimp1 dependent, express type 2 cytokines, and share features of visceral adipose tissue Treg cells. Bcl6-deficient Treg cells are more susceptible, and Blimp1-deficient Treg cells are resistant, to acquiring the ST2+ Treg–cell phenotype in vitro and in vivo in response to IL-33. Bcl6-deficient ST2+ Treg cells, but not Bcl6-deficient ST2+ conventional T cells, strongly promote allergic airway inflammation when transferred into recipient mice. Lastly, ST2 is required for the exacerbated allergic airway inflammation in Bcl6fl/fl Foxp3-Cre mice. Conclusions During allergic airway inflammation, Bcl6 and Blimp1 play dual roles in regulating Tfr-cell activity in the germinal center and in the development of ST2+ Treg cells that promote type 2 cytokine responses.
Comparative Analysis of Alternative Splicing Profiles in Th Cell Subsets Reveals Extensive Cell Type–Specific Effects Modulated by a Network of Transcription Factors and RNA-Binding Proteins
(American Association of Immunologists, 2021-09-28) Mir, Quoseena; Lakshmipati, Deepak K.; Ulrich, Benjamin J.; Kaplan, Mark H.; Janga, Sarath Chandra; Biomedical Engineering and Informatics, Luddy School of Informatics, Computing, and Engineering
Alternative splicing (AS) plays an important role in the development of many cell types; however, its contribution to Th subsets has been clearly defined. In this study, we compare mice naive CD4+ Th cells with Th1, Th2, Th17, and T regulatory cells and observed that the majority of AS events were retained intron, followed by skipped-exon events, with at least 1200 genes across cell types affected by AS events. A significant fraction of the AS events, especially retained intron events from the 72-h time point, were no longer observed 2 wk postdifferentiation, suggesting a role for AS in early activation and differentiation via preferential expression of specific isoforms required during T cell activation, but not for differentiation or effector function. Examining the protein consequence of the exon-skipping events revealed an abundance of structural proteins encoding for intrinsically unstructured peptide regions, followed by transmembrane helices, β strands, and polypeptide turn motifs. Analyses of expression profiles of RNA-binding proteins (RBPs) and their cognate binding sites flanking the discovered AS events revealed an enrichment for specific RBP recognition sites in each of the Th subsets. Integration with publicly available chromatin immunoprecipitation sequencing datasets for transcription factors support a model wherein lineage-determining transcription factors impact the RBP profile within the differentiating cells, and this differential expression contributes to AS of the transcriptome via a cascade of cell type-specific posttranscriptional rewiring events.
A conserved enhancer regulates Il9 expression in multiple lineages
(Nature Research, 2018-11-15) Koh, Byunghee; Qayum, Amina Abdul; Srivastava, Rajneesh; Fu, Yongyao; Ulrich, Benjamin J.; Janga, Sarath Chandra; Kaplan, Mark H.; Pediatrics, School of Medicine
Cytokine genes are regulated by multiple regulatory elements that confer tissue-specific and activation-dependent expression. The cis-regulatory elements of the gene encoding IL-9, a cytokine that promotes allergy, autoimmune inflammation and tumor immunity, have not been defined. Here we identify an enhancer (CNS-25) upstream of the Il9 gene that binds most transcription factors (TFs) that promote Il9 gene expression. Deletion of the enhancer in the mouse germline alters transcription factor binding to the remaining Il9 regulatory elements, and results in diminished IL-9 production in multiple cell types including Th9 cells, and attenuates IL-9-dependent immune responses. Moreover, deletion of the homologous enhancer (CNS-18) in primary human Th9 cultures results in significant decrease of IL-9 production. Thus, Il9 CNS-25/IL9 CNS-18 is a critical and conserved regulatory element for IL-9 production.
ERG functionally overlaps with other Ets proteins in promoting TH9 cell expression of Il9 during allergic lung inflammation
(American Association of Immunologists, 2023) Kharwadkar, Rakshin; Ulrich, Benjamin J.; Chu, Michelle; Koh, Byunghee; Hufford, Matthew M.; Fu, Yongyao; Birdsey, Graeme M.; Porse, Bo T.; Randi, Anna M.; Kaplan, Mark H.; Biochemistry and Molecular Biology, School of Medicine
CD4+ TH cells develop into subsets that are specialized in the secretion of particular cytokines to mediate restricted types of inflammation and immune responses. Among the subsets that promote development of allergic inflammatory responses, IL-9-producing TH9 cells are regulated by a number of transcription factors. We have previously shown that the E26 transformation-specific (Ets) family members PU.1 and Ets translocation variant 5 (ETV5) function in parallel to regulate IL-9. In this study we identified a third member of the Ets family of transcription factors, Ets-related gene (ERG), that mediates IL-9 production in TH9 cells in the absence of PU.1 and ETV5. Chromatin immunoprecipitation assays revealed that ERG interaction at the Il9 promoter region is restricted to the TH9 lineage and is sustained during murine TH9 polarization. Knockdown or knockout of ERG during murine or human TH9 polarization in vitro led to a decrease in IL-9 production in TH9 cells. Deletion of ERG in vivo had modest effects on IL-9 production in vitro or in vivo. However, in the absence of PU.1 and ETV5, ERG was required for residual IL-9 production in vitro and for IL-9 production by lung-derived CD4 T cells in a mouse model of chronic allergic airway disease. Thus, ERG contributes to IL-9 regulation in TH9 cells.
Expression Efficiency of Multiple Il9 Reporter Alleles Is Determined by Cell Lineage
(American Association of Immunologists, 2020-05-21) Kharwadkar, Rakshin; Ulrich, Benjamin J.; Abdul Qayum, Amina; Koh, Byunghee; Licona-Limón, Paula; Flavell, Richard A.; Kaplan, Mark H.; Biochemistry and Molecular Biology, School of Medicine
Generation of allelic gene reporter mice has provided a powerful tool to study gene function in vivo. In conjunction with imaging technologies, reporter mouse models facilitate studies of cell lineage tracing, live cell imaging, and gene expression in the context of diseases. Although there are several advantages to using reporter mice, caution is important to ensure the fidelity of the reporter protein representing the gene of interest. In this study, we compared the efficiency of two Il9 reporter strains Il9citrine and Il9GFP in representing IL-9-producing CD4+ TH9 cells. Although both alleles show high specificity in IL-9-expressing populations, we observed that the Il9GFP allele visualized a much larger proportion of the IL-9-producing cells in culture than the Il9citrine reporter allele. In defining the mechanistic basis for these differences, chromatin immunoprecipitation and chromatin accessibility assay showed that the Il9citrine allele was transcriptionally less active in TH9 cells compared with the wild-type allele. The Il9citrine allele also only captured a fraction of IL-9-expressing bone marrow-derived mast cells. In contrast, the Il9 citrine reporter detected Il9 expression in type 2 innate lymphoid cells at a greater percentage than could be identified by IL-9 intracellular cytokine staining. Taken together, our findings demonstrate that the accuracy of IL-9 reporter mouse models may vary with the cell type being examined. These studies demonstrate the importance of choosing appropriate reporter mouse models that are optimal for detecting the cell type of interest as well as the accuracy of conclusions.
Interleukin-9 promotes mast cell progenitor proliferation and CCR2-dependent mast cell migration in allergic airway inflammation
(Elsevier, 2023) Pajulas, Abigail; Fu, Yongyao; Cheung, Cherry C. L.; Chu, Michelle; Cannon, Anthony; Alakhras, Nada; Zhang, Jilu; Ulrich, Benjamin J.; Nelson, Andrew S.; Zhou, Baohua; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
Allergic asthma is a chronic lung disease characterized by airway hyperresponsiveness and cellular infiltration that is exacerbated by immunoglobulin E-dependent mast cell (MC) activation. Interleukin-9 (IL-9) promotes MC expansion during allergic inflammation but precisely how IL-9 expands tissue MCs and promotes MC function is unclear. In this report, using multiple models of allergic airway inflammation, we show that both mature MCs (mMCs) and MC progenitors (MCp) express IL-9R and respond to IL-9 during allergic inflammation. IL-9 acts on MCp in the bone marrow and lungs to enhance proliferative capacity. Furthermore, IL-9 in the lung stimulates the mobilization of CCR2+ mMC from the bone marrow and recruitment to the allergic lung. Mixed bone marrow chimeras demonstrate that these are intrinsic effects in the MCp and mMC populations. IL-9-producing T cells are both necessary and sufficient to increase MC numbers in the lung in the context of allergic inflammation. Importantly, T cell IL-9-mediated MC expansion is required for the development of antigen-induced and MC-dependent airway hyperreactivity. Collectively, these data demonstrate that T cell IL-9 induces lung MC expansion and migration by direct effects on the proliferation of MCp and the migration of mMC to mediate airway hyperreactivity.
Pancreas transplantation for Cystic Fibrosis: A Frequently Missed Opportunity
(Wiley, 2021-09) Fridell, Jonathan A.; Bozic, Molly A.; Ulrich, Benjamin J.; Lutz, Andrew J.; Powelson, John A.; Surgery, School of Medicine
Cystic fibrosis (CF) is an inherited autosomal recessive disorder. Despite optimized therapy, the majority of affected individuals ultimately die of respiratory failure. As patients with CF are living longer, extra-pulmonary manifestations may develop including pancreatic failure, which manifests as exocrine insufficiency, and CF related diabetes (CFRD). Both of these can be managed through pancreas transplantation. Pancreas transplantation is usually performed in combination with another organ, most often with a kidney transplant for end-stage diabetic nephropathy. In the CF patient population, the two settings where inclusion of a pancreas transplant should be considered would be in combination with a lung transplant for CF pulmonary disease, or in combination with a liver for CF related liver disease with cirrhosis. This report will discuss this topic in detail, including a review of the literature regarding combinations of lung/pancreas and liver/pancreas transplant.

Browsing by Author "Ulrich, Benjamin J."

Results Per Page

Sort Options