With an estimated two billion people infected with soil-transmitted helminthes worldwide, this group of parasitic infections represents a significant public health and economic concern. While CD4+ T helper type 2 (TH2) cell responses characterized by IL-4 and IL-13 production are required for protective immunity to intestinal helminth infection, the innate immune responses that promote TH2 cell responses in vivo remain incompletely understood. The goals of this proposal are to interrogate the influence of the epithelial cell-derived cytokine thymic stromal lymphopoietin (TSLP) on regulating basophil responses and the differentiation of TSLP- responsive progenitor cell populations and to assess the role of these cells in influencing TH2 cytokine- dependent host protective immunity following intestinal nematode infection. Employing Trichuris muris and Trichinella spiralis, two well-characterized experimental murine models of human helminth infections, our preliminary studies identified that TSLP selectively promotes basophil responses and basophil-restricted expression was sufficient to partially restore TH2 cell responses and host protective immunity following helminth infection in susceptible mice. In addition, we identified a population of TSLP-elicited progenitor-like cells in the periphery that express the TSLP receptor (TSLPR), exhibit multipotent potential and differentiate to effector cells that produce IL-4 and IL-13. Collectively these data provide insight into two previously unrecognized pathways by which TSLP-dependent basophils and peripheral progenitor-like populations are critical regulators of anti-helminth immunity. Employing a series of novel adoptive transfers and in vivo depletion approaches, Aim 1 of this proposal will utilize experimental Trichuris or Trichinella infection in mice to determine how TSLP regulates innate immune responses required for host protective immunity.
Aim 2 of this proposal will utilize similar adoptive transfer studies in mice, in conjunction with cutting edge studies in human patients and humanized mice (hu-mice), to assess the influence of TSLP on progenitor cell responses in the periphery. The results of these studies will provide a framework to test the therapeutic potential of manipulating TSLP-elicited basophils or TSLP-elicited progenitor-like cells in the promotion of anti-helminth immunity. We anticipate that defining the contribution of TSLP-elicited basophils and progenitor-like cells to anti-helminth immunity will direct future efforts to design and improve the efficacy of anti-parasitic oral vaccines and to dampen TH2 cytokine-associated inflammation in the context of asthma and other allergic diseases.
Soil transmitted helminth parasites are a significant public health concern, with approximately two billion people infected worldwide. The goals of this proposal are to understand the influence of a soluble molecule of the immune system called thymic stromal lymphopoietin (TSLP) on regulating immune cell development and function required for protective immunity to these parasitic infections. The results of these studies will help to inform the design of successful new anti-parasitic drugs, vaccines and immunotherapies to fight these infectious diseases.
|Moriyama, Saya; Brestoff, Jonathan R; Flamar, Anne-Laure et al. (2018) ?2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359:1056-1061|
|Veiga-Fernandes, Henrique; Artis, David (2018) Neuronal-immune system cross-talk in homeostasis. Science 359:1465-1466|
|Meisel, Jacquelyn S; Sfyroera, Georgia; Bartow-McKenney, Casey et al. (2018) Commensal microbiota modulate gene expression in the skin. Microbiome 6:20|
|Chu, Coco; Moriyama, Saya; Li, Zhi et al. (2018) Anti-microbial Functions of Group 3 Innate Lymphoid Cells in Gut-Associated Lymphoid Tissues Are Regulated by G-Protein-Coupled Receptor 183. Cell Rep 23:3750-3758|
|Klose, Christoph S N; Mahlakõiv, Tanel; Moeller, Jesper B et al. (2017) The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549:282-286|
|Blander, J Magarian; Longman, Randy S; Iliev, Iliyan D et al. (2017) Regulation of inflammation by microbiota interactions with the host. Nat Immunol 18:851-860|
|Wallrapp, Antonia; Riesenfeld, Samantha J; Burkett, Patrick R et al. (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549:351-356|
|Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure et al. (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17:656-65|
|Alex, Aneesh; Tait Wojno, Elia D; Artis, David et al. (2016) Label-Free Imaging of Eosinophilic Esophagitis Mouse Models Using Optical Coherence Tomography. Methods Mol Biol 1422:127-36|
|Rak, Gregory D; Osborne, Lisa C; Siracusa, Mark C et al. (2016) IL-33-Dependent Group 2 Innate Lymphoid Cells Promote Cutaneous Wound Healing. J Invest Dermatol 136:487-496|
Showing the most recent 10 out of 49 publications