Browsing by Author "Nelson, Andrew S."

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    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.
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    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.
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    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.
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    Selectin Dependence of Allergic Skin Inflammation Is Diminished by Maternal Atopy
    (American Association of Immunologists, 2021-08-25) Khan, Ibrahim M.; Ulrich, Benjamin J.; Nelson, Andrew S.; Sehra, Sarita; Kansas, Geoffrey S.; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
    Allergic skin inflammation requires the influx of inflammatory cells into the skin. Extravasation of leukocytes into the skin requires interactions between endothelial selectins and their glycan ligands on the surface of leukocytes. Selectin-ligand formation requires the activity of several glycosyltransferases, including Fut7 In this report, we tested the importance of Fut7 for the development of allergic skin inflammation in the Stat6VT transgenic mouse model. We observed that Fut7 deficiency was protective but did not eliminate disease. Segregation of the data by gender of the parent that transmitted the Stat6VT transgene, but not by gender of the pups, which were analyzed for disease, revealed that the protective effects of Fut7 deficiency were significantly greater when dams were Stat6VT negative. In contrast, in mice from litters of Stat6VT+ dams, Fut7 deficiency resulted in only modest protection. These findings indicate that pups from atopic dams exhibit a greater propensity for allergic disease, similar to observations in humans, and that the effect of maternal atopy is due to enhanced selectin-independent mechanisms of leukocyte recruitment in their offspring. Together, these results demonstrate that Fut7 deficiency can be protective in a model of atopic dermatitis but that maternal atopy diminishes these protective effects, suggesting alternative pathways for leukocyte recruitment in the absence of Fut7 enzyme activity. These observations have implications for understanding how the environment in utero predisposes for the development of allergic disease.
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    STAT4 is expressed in neutrophils and promotes antimicrobial immunity
    (American Society for Clinical Investigation, 2021-07-22) Mehrpouya-Bahrami, Pegah; Moriarty, Alina K.; De Melo, Paulo; Keeter, W. Coles; Alakhras, Nada S.; Nelson, Andrew S.; Hoover, Madeline; Barrios, Maria S.; Nadler, Jerry L.; Serezani, C. Henrique; Kaplan, Mark H.; Galkina, Elena V.; Microbiology and Immunology, School of Medicine
    Signal transducer and activator of transcription 4 (STAT4) is expressed in hematopoietic cells and plays a key role in the differentiation of T helper 1 cells. Although STAT4 is required for immunity to intracellular pathogens, the T cell-independent protective mechanisms of STAT4 are not clearly defined. In this report, we demonstrate that STAT4-deficient mice were acutely sensitive to methicillin-resistant Staphylococcus aureus (MRSA) infection. We show that STAT4 was expressed in neutrophils and activated by IL-12 via a JAK2-dependent pathway. We demonstrate that STAT4 was required for multiple neutrophil functions, including IL-12-induced ROS production, chemotaxis, and production of the neutrophil extracellular traps. Importantly, myeloid-specific and neutrophil-specific deletion of STAT4 resulted in enhanced susceptibility to MRSA, demonstrating the key role of STAT4 in the in vivo function of these cells. Thus, these studies identify STAT4 as an essential regulator of neutrophil functions and a component of innate immune responses in vivo.
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    γδ T Cell‒Mediated Wound Healing Is Diminished by Allergic Skin Inflammation
    (Elsevier, 2022-10) Wang, Jocelyn; Pajulas, Abigail; Fu, Yongyao; Adom , Djamilatou; Zhang, Wenwu; Nelson, Andrew S.; Spandau, Dan F.; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
    Atopic dermatitis results in profound changes in the function of the skin that include diminished barrier function and altered production of antimicrobial peptides. Our previous work in a model of allergic skin inflammation identified a defect in the wound healing process that was dependent on IL-4. In this report, we show that allergic skin inflammation results in a dramatic decrease in the presence of the Vγ3+ dendritic epidermal T-cell (DETC) population of γδ T cells in the skin. In mice that express an active signal transducer and activator of transcription 6 in T cells, DETCs are lost early in life. The loss of DETCs is entirely dependent on IL-4 and is recovered with a genetic deficiency of IL-4. Moreover, injection of IL-4 into wild-type mice results in acute loss of the DETC population. A similar loss of DETCs was observed in mice treated topically with MC903. Wounding of skin from Stat6VT-transgenic or MC903-treated mice resulted in decreased production of DETC-dependent cytokines in the skin, coincident with diminished wound closure. Importantly, intradermal injection of the DETC-produced cytokine fibroblast GF 7 rescued the rate of wound closure in mice with allergic skin inflammation. Together, these results suggest that the atopic environment diminishes prohealing T-cell populations in the skin, resulting in attenuated wound healing responses.