Th17 cell differentiation: unique signaling pathways and mechanisms

Naïve T cells receive multiple signals that drive them to proliferate and change their function after antigen recognition.  They can then travel around the body and are armed to respond to infection, or in the case of autoimmunity respond to self proteins. We recently found that CD28 costimulation is inhibitory for human Th17 cell development, and that CD28-Akt tunes Th17 cell differentiation  (Revu et al, Cell Reports 2018). This was initially surprising as CD28 costimulation is considered a critical ‘signal 2’ for T cell activation. However, we realized the cytokines IL-23 and IL-1b (‘signal 3’) compensate for some of the functions usually provided by CD28, including increased glucose uptake and glycolysis capacity. Ongoing work in our lab is now focused on understanding how CD28 and other signaling pathways modulate the Th17 program, and particularly we are interested in the unique signaling pathways that promote Th17 differentiation and IL-17 production in humans versus mice. To make our studies more physiological, we are collaborating with Dr Xia, Associate Professor of Neurology at University of Pittsburgh, to test our findings in myelin-activated Th17 cells from patients with multiple sclerosis. To complement these in vitro assays, we are reverse-translating our human findings to generate ‘humanized CD28’ mice so that we can address questions of tolerance and autoimmune Th17 induction in vivo in a relevant system.

Th17 interactions with lymph node stromal cells, and consequences for adaptive immunity

Stromal cells are essentially fibroblasts, you may think of them as the cells that produce collagen to provide structure to tissues. However, recent advances in single cell sequencing have highlighted the functional heterogeneity and tissue specialization of fibroblast subpopulations. In secondary lymphoid organs, stromal cells called FRC help organize the lymph node by producing chemokines and cytokines necessary for recruitment and survival of lymphocytes. Of particular interest to us, FRC also help modulate adaptive immunity. When an immune response is initiated, e.g. following immunization, the local LN swells and FRC proliferate to be able to continue to support the increased cell volume. We recently discovered that local IL-17 produced by differentiating Th17 cells is critical to support the proliferation and survival of FRC in response to LN inflammation. Unexpectedly, loss of IL-17 signaling led to nutrient stress and major defects in metabolic activity of FRC. This was exciting because it revealed a previously unknown role for IL-17 in driving metabolic reprogramming in activated stroma (Majumder et al, Nature Immunology 2019).  IL-17 dependent FRC activation was important for optimal antibody production in autoimmune and infectious settings. Recently we showed that non-specific gut inflammation results in FRC training through IL-17, and upon subsequent infection with a previously unencountered pathogen, FRC training leads to an improved B cell response (Wu et al, Science Immunology 2021). Surprisingly, enhanced immunity also reduced the gut inflammation normally required to clear infection, which turned out to be due to increased IL-10 production by B cells after training. These studies raise a number of questions that we are now actively pursuing, including how IL-17 signaling in FRC leads to enhanced B cell immunity and mechanisms of FRC metabolic boosting, and how FRC training can impact adaptive immune response during other infections (including Th1 and Th2 drivers) and autoimmunity.

BSc (Immunology) University of Glasgow, Scotland, UK
PhD University of Edinburgh, Scotland, UK

Dr. McGeachy assumes her position as Associate Professor in the Department of Microbiology and Immunology in July 2022. Dr. McGeachy completed her undergraduate and graduate training in Immunology in Scotland, before moving to California for postdoctoral training at DNAX/Schering-Plough Biopharma, where she was promoted to Senior Scientist before returning to academia. She established her independent research program at the University of Pittsburgh in 2012, and was promoted to Associate Professor with tenure in 2018. Her lab studies Th17 cells in autoimmune and infectious disease, including recent forays into investigating how interactions between Th17 cells and stromal cells in lymph nodes modulate adaptive immunity.

Section Editor, Journal of Immunology

Member, American Association of Immunologists

Member, International Cytokine and Interferon Society

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Selected recent publications:

•    Wu D, Poholek CH, Revu S, Liu Q, Majumder S, Rothstein D, McGeachy MJ* “IL-17 dependent fibroblastic reticular cell training boosts host-protective immunity to mucosal infection through IL-10 producing B cells” Science Immunology 2021 PMID: 34919443
•    Majumder S, McGeachy MJ  “IL-17 in Health and Disease: Good Intentions gone awry” Annual Reviews of Immunology, April 2021 PMID: 33577346
•    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 PMID: 32697822
•    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
•    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 Immunology 2019 PMID: 31209103
•    Revu S, Wu J, Henkel M, Rittenhouse N, Menk A, Delgoffe GM, Poholek AC, McGeachy MJ* “IL-23 and IL-1ß drive human Th17 cell differentiation and metabolic reprogramming in absence of CD28 costimulation” Cell Reports 2018 PMID: 29514093