Slide 1: Role of IL-33 in Modulating Human Allergen Specific Pathogenic CD4+ T Cell Responses
ROLE OF IL‐33 IN MODULATING HUMAN ALLERGEN SPECIFIC PATHOGENIC CD4+T CELL RESPONSES Nahir Garabatos, PhD Postdoctoral Research Associate Dr. Erik Wambre’s Lab Benaroya Research Institute, Seattle WA
Slide 2: IL-33 plays an important role in allergy and inflammation
IL‐33 plays an important role in allergy and inflammation • IL‐33, also called alarmin, is a pro‐ inflammatory cytokine induced by inflammatory stimulation leading to Type 2 immune responses in tissue epithelial cells. • IL‐33 mediates its biological effects via IL‐1 receptor‐like 1 (ST2). • IL‐33 a
Slide 3: A distinct TH2 cell subset is associated with type I allergic diseases
A distinct TH2 cell subset is associated with type I allergic diseases Allergic individuals 10 000 P=0.001 35% TH2A cell memory CD4+ T cells subset # TH2A cells per 106 CD49d CRTH2 CD4 1 000 CD45RB CD27 CD161 Non-atopic individuals 100 35% TH2A cell subset CD49d CRTH2 10 CD4 CD45RB CD27 CD161 • CD27
Slide 4: Allergic disease related differences emerged in the TH2 cell responses
Allergic disease related differences emerged in the TH2 cell responses PPARG TH2A cell subset produced more transcript of IL‐5 and IL‐9 compared to conventional TH2 cells. They also selectively expressed IL‐33R (IL1RL1 or ST2) and may differentially contribute to atopic diseases (TH2 driven path
Slide 5: Role of IL-33 in promoting the activity of peanut-specific TH2A cells: Methods
Role of IL‐33 in promoting the activity of peanut‐specific TH2A cells: Methods • Peanut Allergy was used as an experimental model (10 peanut allergic patients). • CD154 upregulation following short stimulation of PBMCs with Peanut extract was used to track peanut reactive T cells and evaluate influe
Slide 6: Peanut specific TH2A cells express high RNA levels of IL-33 Receptor
Peanut specific TH2A cells express high RNA levels of IL‐33 Receptor Within Peanut Reactive (CD154+ ) Memory CD4+ T cells CD154 IL‐33 R (ST2) FC (Relative Units) CD27 CRTH2 CD161 100 % peanut-specific T cells 80 60 40 20 0 Peanut reactive T cells (CD154+) from patients fall into 2 subsets accordin
Slide 7: Cytokine profiles between CD27- and CD27+ allergen-specific T cell subsets are highly divergent
Cytokine profiles between CD27‐ and CD27+ allergen‐specific T cell subsets are highly divergent: IL‐4 IL‐5 IL‐9 IL‐13 Peanut Reactive T cells CD154+ CD154+CD27+ CD27 CD154+CD27- CD154 N=10 Peanut Patients CD27‐ peanut specific T cells CD27 negative Peanut specific T cell CD27+ peanut specific T ce
Slide 8: IL-33 enhance pro-inflammatory function of allergen specific TH2A cell responses
IL‐33 enhance pro‐inflammatory function of allergen specific TH2A cell responses CD154+ TH2A cell subset CD154‐ TH2A cell subset +IL33 +IL33 IL‐5 IL‐9 IL‐4 Upon TCR stimulation, IL‐33 regulate the pathogenicity of allergen‐specific CD4+ TH2A cells.
Slide 9: Allergen specific TH2A cells are critical target of IL-33 in allergic inflammation
Allergen specific TH2A cells are critical target of IL‐33 in allergic inflammation IL‐5 IL‐4 ‐ IL‐33 + IL‐33 N=10 Peanut Patients IL‐33 selectively amplify peanut specific TH2A cell responses As expected in adaptive immunity, IL‐33‐induced upregulation of IL‐4 and IL‐5 require previous TCR trigg
Slide 10: Allergen specific TH2A cells are critical target of IL-33 in allergic inflammation
Allergen specific TH2A cells are critical target of IL‐33 in allergic inflammation Extract Xtr+IL‐33 N=2 Peanut Patients IL‐5 IL‐4 IL‐13 Upon TCR stimulation, IL‐33 selectively enhances TH2 cytokine expression and production by allergen‐specific TH2A cells
Slide 11: IL-33 represent an attractive therapeutic target
IL‐33 represent an attractive therapeutic target Peanut Tissue IL‐33 ILC2 Mast Cell IL‐5 APC IL‐4 Peanut TH2A Lymph nodes APC Peanut TCR Expression of effector cytokines by allergen‐ TH2A specific TH2 cells depends on IL‐33 cytokine at sites of tissue damage, revealing a tissue checkpoint that regul
Slide 12: Conclusions
Conclusions TH2A cell subset represents a phenotypically and functionally distinct TH2 subpopulation in atopic individuals that includes all allergen‐specific TH2 cells and specifically express IL‐33 receptor (ST2). Production of effector cytokines by activated allergen‐specific TH2A cells is mo
Slide 13: Acknowledgements
Acknowledgements Wambre laboratory: Anaptys Bio: Erik Wambre Marco Londei Veronique Bajzik Blake Rust Kelly Aldridge Sam Skinner Hannah Deberg Virginia Mason: David Robinson Mary Farrington David Jeong Genomic core: Kimberly O’Brien Peter Linsley Vivian Gersuk Clinical core: Gina Marchesini Kavitha
Slide 14: Benaroya Research Institute
Vy BENAROYA RESEARCH INSTITUTE A A. Virginia Mason BRING IT ON. BenaroyaResearch.org