Mandy J. McGeachy, Ph.D.
Campus: BST South, S719, 3500 Terrace Street
Pittsburgh, PA 15261
- BSc, University of Glasgow, Scotland, UK, 2001
- Ph.D., University of Edinburgh, Scotland, UK, 2005
- Postdoc, Schering-Plough Biopharma/DNAX, 2009
- Associate Professor, Division of Rheumatology & Clinical Immunology
Th17 cells cause chronic tissue inflammation in autoimmune diseases like psoriasis, multiple sclerosis and Crohn’s disease. However, Th17 cells and other ‘type-17’ cells provide vital protection against commensals and opportunistic pathogens at barrier surfaces, and also aid in wound repair. Many of these effects are achieved through production of IL-17. Perhaps due to these dual functions of Th17 cells, therapies targeted towards the IL-17 pathway are highly efficacious in some diseases, but have had mixed results in others. The McGeachy lab studies how inflammatory Th17 cells are generated, regulated and mediate their effects through IL-17 in different tissues, with the goal of determining the best approaches to modulate Th17-driven pathology while conserving the beneficial protective roles of Th17 cells. We use models of autoimmune disease and infection, along with human cell in vitro cultures.
Key questions being addressed:
1) Molecular mechanisms that regulate Th17 differentiation in humans, with a focus on the interplay between costimulatory and cytokine signaling,
2) Functional regulators of in vivo Th17 effector cell pathogenicity in CNS, gut and lymphoid tissues,
3) Regulation of Th17 migration in different tissues,
4) Th17: tissue interactions that lead to stromal cell remodeling during chronic inflammation.
Poholek CH, Raphael I, Wu D, Revu S, Rittenhouse N, Uche UU, Majumder S, Kane LP, Poholek AC, McGeachy MJ “Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen” Journal of Experimental Medicine 2020
Majumder S, Amatya N, Revu S, Jawale CV, Rittenhouse N, Menk A, Raphael I, Baty CJ, Siebenlist U, Hand T, Delgoffe G,Poholek A, Gaffen SL, Biswas PS, McGeachy MJ.IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival. Nature Immunology 2019
Hernandez Mir G, Raphael I, Revu S, Poholek C, Avery L, Hawse WF, Kane LP, McGeachy MJ“The Alzheimer’s Disease-associated protein BACE1 modulates T cell activation and Th17 function” Journal of Immunology2019
Revu S, Wu J, Henkel M, Rittenhouse N, Menk A, Delgoffe GM, Poholek AC, McGeachy MJ “IL-23 and IL-1b drive human Th17 cell differentiation and metabolic reprogramming in absence of CD28 costimulation” Cell Reports 2018
Hernandez Mir G, McGeachy MJ. “CD73 is expressed by inflammatory Th17 cells in experimental autoimmune encephalomyelitis but does not limit differentiation or pathogenesis” Plos One 2017
Singh D, Henkel M, Sendon BB, Feng J, Fabio A, Metes D, Moreland LW, McGeachy MJ. “Analysis of CXCR5+Th17 cells in relation to disease activity and TNF inhibitor therapy in Rheumatoid Arthritis”. Scientific Reports 2016
Du F, Garg AV, Kosar K, Majumder S, Kugler DG, Mir GH, Maggio M, Henkel M, Lacy-Hulbert A, McGeachy MJ “Inflammatory Th17 Cells Express Integrin αvβ3 for Pathogenic Function” Cell Reports, 2016