IU Indianapolis ScholarWorks :: Browsing by Author "Kaplan, Mark H."

Browsing by Author "Kaplan, Mark H."

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A high-resolution view of the immune and stromal cell response to Haemophilus ducreyi infection in human volunteers
(American Society for Microbiology, 2025) Brothwell, Julie A.; Wei, Yuhui; Wang, Jia; Guo, Tingbo; Zhang, Chi; Fortney, Kate R.; Duplantier, Rory; Chen, Li; Batteiger, Teresa A.; Kaplan, Mark H.; Spinola, Stanley M.; Cao, Sha; Microbiology and Immunology, School of Medicine
Haemophilus ducreyi causes the genital ulcer disease chancroid and cutaneous ulcers in children. To study its pathogenesis, we developed a human challenge model in which we infect the skin on the upper arm of human volunteers with H. ducreyi to the pustular stage of disease. The model has been used to define lesional architecture, describe the immune infiltrate into the infected sites using flow cytometry, and explore the molecular basis of the immune response using bulk RNA-seq. Here, we used single cell RNA-seq (scRNA-seq) and spatial transcriptomics to simultaneously characterize multiple cell types within infected human skin and determine the cellular origin of differentially expressed transcripts that we had previously identified by bulk RNA-seq. We obtained paired biopsies of pustules and wounded (mock infected) sites from five volunteers for scRNA-seq. We identified 13 major cell types, including T- and NK-like cells, macrophages, dendritic cells, as well as other cell types typically found in the skin. Immune cell types were enriched in pustules, and some subtypes within the major cell types were exclusive to pustules. Sufficient tissue specimens for spatial transcriptomics were available from four of the volunteers. T- and NK-like cells were highly associated with multiple antigen presentation cell types. In pustules, type I interferon stimulation was high in areas that were high in antigen presentation-especially in macrophages near the abscess-compared to wounds. Together, our data provide a high-resolution view of the cellular immune response to the infection of the skin with a human pathogen. IMPORTANCE: A high-resolution view of the immune infiltrate due to infection with an extracellular bacterial pathogen in human skin has not yet been defined. Here, we used the human skin pathogen Haemophilus ducreyi in a human challenge model to identify on a single cell level the types of cells that are present in volunteers who fail to spontaneously clear infection and form pustules. We identified 13 major cell types. Immune cells and immune-activated stromal cells were enriched in pustules compared to wounded (mock infected) sites. Pustules formed despite the expression of multiple pro-inflammatory cytokines, such as IL-1β and type I interferon. Interferon stimulation was most evident in macrophages, which were proximal to the abscess. The pro-inflammatory response within the pustule may be tempered by regulatory T cells and cells that express indoleamine 2,3-dioxygenase, leading to failure of the immune system to clear H. ducreyi.
Age-related decline in LEPR+ hematopoietic stem cell function
(Springer Nature, 2023) Trinh, Thao; Ropa, James; Cooper, Scott; Aljoufi, Arafat; Sinn, Anthony; Capitano, Maegan; Broxmeyer, Hal E.; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
Allergic Airway Disease in Mice Alters T and B Cell Responses during an Acute Respiratory Poxvirus Infection
(Public Library of Science, 2013-04-19) Walline, Crystal C.; Sehra, Sarita; Fisher, Amanda J.; Guindon, Lynette M.; Kratzke, Ian M.; Montgomery, Jessica B.; Lipking, Kelsey P.; Glosson, Nicole L.; Benson, Heather L.; Sandusky, George E.; Wilkes, David S.; Brutkiewicz, Randy R.; Kaplan, Mark H.; Blum, Janice S.; Microbiology and Immunology, School of Medicine
Pulmonary viral infections can exacerbate or trigger the development of allergic airway diseases via multiple mechanisms depending upon the infectious agent. Respiratory vaccinia virus transmission is well established, yet the effects of allergic airway disease on the host response to intra-pulmonary vaccinia virus infection remain poorly defined. As shown here BALB/c mice with preexisting airway disease infected with vaccinia virus developed more severe pulmonary inflammation, higher lung virus titers and greater weight loss compared with mice inoculated with virus alone. This enhanced viremia was observed despite increased pulmonary recruitment of CD8(+) T effectors, greater IFNγ production in the lung, and high serum levels of anti-viral antibodies. Notably, flow cytometric analyses of lung CD8(+) T cells revealed a shift in the hierarchy of immunodominant viral epitopes in virus inoculated mice with allergic airway disease compared to mice treated with virus only. Pulmonary IL-10 production by T cells and antigen presenting cells was detected following virus inoculation of animals and increased dramatically in allergic mice exposed to virus. IL-10 modulation of host responses to this respiratory virus infection was greatly influenced by the localized pulmonary microenvironment. Thus, blocking IL-10 signaling in virus-infected mice with allergic airway disease enhanced pulmonary CD4(+) T cell production of IFNγ and increased serum anti-viral IgG1 levels. In contrast, pulmonary IFNγ and virus-specific IgG1 levels were reduced in vaccinia virus-treated mice with IL-10 receptor blockade. These observations demonstrate that pre-existing allergic lung disease alters the quality and magnitude of immune responses to respiratory poxviruses through an IL-10-dependent mechanism.
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.
Altered STAT4 isoform expression in patients with inflammatory bowel disease.
(Wolters Kluwer, 2015-10) Jabeen, Rukhsana; Miller, Lucy; Yao, Weiguo; Gupta, Sandeep; Steiner, Steven; Kaplan, Mark H.; Department of Pediatrics, IU School of Medicine
BACKGROUND & AIMS: Crohn’s disease (CD) and ulcerative colitis (UC) are major forms of inflammatory bowel disease (IBD) and pathogenesis involves a complex interplay between genetic, environmental and immunological factors. We evaluated isoform expression of the IL-12-activated transcription factor STAT4 in children with CD and UC. METHODS: We performed a study where we collected biopsy samples from both newly diagnosed CD and UC patients. We further collected blood samples from newly diagnosed CD and UC patients as well as patients who had a flare-up after being in clinical remission, and examined the ratios of STAT4β/STAT4α mRNA. In addition to STAT4 isoforms we measured the expression of the cytokines TNFα, IFNγ, GM-CSF and IL-17 using PCR of biopsy samples and multiplex analysis of patient serum samples. RESULTS: Ratios of STAT4β/STAT4α were increased in specific GI tract segments in both CD and UC patients that correlate with location and severity of inflammation. In contrast, we did not observe changes in STAT4β/STAT4α ratios in biopsy specimens from eosinophilic esophagitis patients. We also observed increased STAT4β/STAT4α ratios in the peripheral blood mononuclear cells of UC and CD patients, compared to healthy controls. Ratios were normalized after patient treatment with steroids. CONCLUSIONS: Collectively, these data indicate that STAT4 isoforms could be an important non-invasive biomarker in the diagnosis and treatment of IBD, and that expression of these isoforms might provide further insight into the pathogenesis of IBD.
An IL-23-STAT4 pathway is required for the proinflammatory function of classical dendritic cells during CNS inflammation
(National Academy of Sciences, 2024) Alakhras, Nada S.; Zhang, Wenwu; Barros, Nicolas; Sharma, Anchal; Ropa, James; Priya, Raj; Yang, X. Frank; Kaplan, Mark H.; Biochemistry and Molecular Biology, School of Medicine
Although many cytokine pathways are important for dendritic cell (DC) development, it is less clear what cytokine signals promote the function of mature dendritic cells. The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of proinflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. To define whether STAT4 is required for intrinsic signaling in mature DC function, we used conditional mutant mice in the EAE model. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the central nervous system. EAE susceptibility was recovered following adoptive transfer of wild-type bone marrow-derived DCs to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4- or IL-23R-deficient DCs. Single-cell RNA-sequencing (RNA-seq) identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define an IL-23-STAT4 pathway in DCs that is key to DC function during inflammatory disease.
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.
Anti-STAT6 CTL activity in Stat6−/− mice: A cautionary tale
(Taylor & Francis, 2013) Kaplan, Mark H.; Cundiff, Judy K.; Smith, Jill Stader; Aldrich, Carla J.; Pediatrics, School of Medicine
The generation of germline gene mutations in mice has been an invaluable tool for experimental biology. However, studying immune responses that develop in the absence of a specific protein that could alter thymic selection complicates experimental interpretations. We observed that CD8(+) T cells from Stat6 (-/-) mice displayed "autoreactivity" to STAT6-expressing cells, associated with specific STAT6 peptides binding to MHC class I molecules. These results suggest caution in interpreting experiments where STAT6-expressing cells are transferred into Stat6 (-/-) mice, or where adoptive transfer of Stat6 (-/-) lymphocytes is performed. Our results further highlight additional considerations when studying immune responses involving cell transfer into gene-deficient mice.
BATF Regulates T Regulatory Cell Functional Specification and Fitness of Triglyceride Metabolism in Restraining Allergic Responses
(American Association of Immunologists, 2021) Xu, Chengxian; Fu, Yongyao; Liu, Sheng; Trittipo, Jack; Lu, Xiaoyu; Qi, Rong; Du, Hong; Yan, Cong; Zhang, Chi; Wan, Jun; Kaplan, Mark H.; Yang, Kai; Pediatrics, School of Medicine
Preserving appropriate function and metabolism in regulatory T (Treg) cells is crucial for controlling immune tolerance and inflammatory responses. Yet how Treg cells coordinate cellular metabolic programs to support their functional specification remains elusive. In this study, we report that BATF couples the TH2-suppressive function and triglyceride (TG) metabolism in Treg cells for controlling allergic airway inflammation and IgE responses. Mice with Treg-specific ablation of BATF developed an inflammatory disorder characterized by TH2-type dominant responses and were predisposed to house dust mite-induced airway inflammation. Loss of BATF enabled Treg cells to acquire TH2 cell-like characteristics. Moreover, BATF-deficient Treg cells displayed elevated levels of cellular TGs, and repressing or elevating TGs, respectively, restored or exacerbated their defects. Mechanistically, TCR/CD28 costimulation enhanced expression and function of BATF, which sustained IRF4 activity to preserve Treg cell functionality. Thus, our studies reveal that BATF links Treg cell functional specification and fitness of cellular TGs to control allergic responses, and suggest that therapeutic targeting of TG metabolism could be used for the treatment of allergic disease.
BATF sustains homeostasis and functionality of bone marrow Treg cells to preserve homeostatic regulation of hematopoiesis and development of B cells
(Frontiers Media, 2023-02-22) Tikka, Chiranjeevi; Beasley, Lindsay; Xu, Chengxian; Yang, Jing; Cooper, Scott; Lechner, Joseph; Gutch, Sarah; Kaplan, Mark H.; Capitano, Maegan; Yang, Kai; Pediatrics, School of Medicine
Bone marrow Treg cells (BM Tregs) orchestrate stem cell niches crucial for hematopoiesis. Yet little is known about the molecular mechanisms governing BM Treg homeostasis and function. Here we report that the transcription factor BATF maintains homeostasis and functionality of BM Tregs to facilitate homeostatic regulation of hematopoiesis and B cell development. Treg-specific ablation of BATF profoundly compromised proportions of BM Tregs associated with reduced expression of Treg effector molecules, including CD44, ICOS, KLRG1, and TIGIT. Moreover, BATF deficiency in Tregs led to increased numbers of hematopoietic stem cells (HSCs), multipotent progenitors (MPPs), and granulocyte-macrophage progenitors (GMPs), while reducing the functionality of myeloid progenitors and the generation of common lymphoid progenitors. Furthermore, Tregs lacking BATF failed to support the development of B cells in the BM. Mechanistically, BATF mediated IL-7 signaling to promote expression of effector molecules on BM Tregs and their homeostasis. Our studies reveal a previously unappreciated role for BATF in sustaining BM Treg homeostasis and function to ensure hematopoiesis.

Browsing by Author "Kaplan, Mark H."

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