Th17 Cells in Health and Disease

Th17 cells are CD4+ T cells that produce the cytokine IL-17. These cells have developed a bad reputation as troublemakers that cause inflammation in autoimmune diseases like psoriasis, multiple sclerosis, or IBD. As the blossoming field of research into Th17 cells has matured, it has become clear that Th17 cells in healthy people are constantly working behind the scenes to maintain microbial homeostasis at exposed surfaces (skin, gut, mouth, eyes etc), and to help with tissue repair following injury.

In the McGeachy lab, we are working to understand how Th17 cells develop and are influenced to be ‘good’ or ‘bad’ in their functions. By studying the signaling pathways and molecules that regulate Th17 cells’ ability to produce IL-17, we hope to figure out how to modulate their function therapeutically1-4. Excitingly, much of this work is now being done with human Th17 cells, including from patients with autoimmune disease.

To better understand TH17 function, the second focus of our lab is to study how IL-17 affects Th17 target cells5.One target of particular interest to us are stromal cells including fibroblastic reticular cells (FRC) in the lymph nodes. FRC are complex and functionally heterogeneous cells that organize the lymphoid tissue architecture and regulate T cell and antibody responses. We recently demonstrated that IL-17 can drive metabolic reprogramming in inactivated lymph node stromal cells during autoimmune inflammation, and that this metabolic shift has important consequences for stromal cell survival and for autoantibody production6.

What We Believe

Follow the Science

Often the most interesting discoveries come from the unexpected data. So proving your PI wrong is encouraged, and new hypotheses and experiments are developed based on data, not dogma.

Foster Diversity and Inclusion

Different cultural, gender, racial and educational backgrounds bring different scientific approaches and insight. We believe that diversity not only makes academic research more interesting and fun, but that it is also critically important to bring innovation and new advances that promote human health. Fostering an inclusive environment where everybody feels valued and heard is an important value for our lab, and Dr.McGeachy aims to be an advocate for women and under-represented minorities in their scientific careers.

Collaborate

By working with wonderful colleagues at Pitt and beyond, we can follow the science into new areas of research, from autoimmunity to infection, T cells to stromal cells to B cells. To us, this is what makes science exciting!

References

1. 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 PMID: 27452457

2. Revu S, Wu J, Henkel M, Rittenhouse N, Menk A, Delgoffe GM, Poholek AC, McGeachy MJ “IL-23 and IL-1drive human Th17 cell differentiation and metabolic reprogramming in absence of CD28 costimulation” Cell Reports 2018 Pubmed PMID: 29514093

3. 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 andTh17 function” Journal of Immunology 2019

4. Catherine Poholek* Itay Raphael*, Dongwen Wu, Shankar K Revu, Natalie Rittenhouse, Uzo Uche, Saikat Majumder, Lawrence Kane, Amanda C Poholek, Mandy J McGeachy “Non-canonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen” Journal of Experimental Medicine, 2020

5. McGeachy MJ, Cua DJ, Gaffen SL “The IL-17 Family of Cytokines in Health and Disease” Immunity 2019 Apr 16;50(4):892-906. PMID: 30995505 (Review invited for Immunity journal’s 25th anniversary special edition focus on cytokines)

6. Majumder SA, Amatya N, Revu S, Jawale CV, Rittenhouse N, Menk A, Kupul S, Du F, Raphael I, Bhattarcharjee A, Siebenlist U, Hand TW, Delgoffe GM, Poholek AC, Gaffen SL, Biswas PS, McGeachy MJ “IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival” Nature Immunology 2019 PMID: 30962593