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Below are some key recent publications from our lab. See all reviews and primary research articles here.

Human IL-17A protein production is controlled through a PIP5K1a-dependent translational checkpoint

Phosphatidylinositols like PIP2 are known to transduce signals from the T cell receptor and costimulatory receptors at the T cell plasma membrane. Here, we unexpectedly found that phosphatidylinositol 4,5-bisphosphate (PIP2) was enriched in the nuclei of human TH17 cells.  We showed that the kinase PIP5K1α drives nuclear PIP2 and that inhibition of PIP5K1α impaired IL-17A production, including in autoimmune Th17 cells from people with Multiple Sclerosis. When we investigated how PIP5K1a is controlling IL-17, we were surprised to find that IL-17 protein was affected without altering either the abundance or stability of IL17A mRNA in TH17 cells. Instead, mass spec analysis revealed that PIP5K1α interacted with ARS2, a nuclear cap-binding complex scaffold protein, to facilitate ARS2 binding to IL17A mRNA to promote IL-17A protein production. These findings highlight a transcription-independent, translation-dependent mechanism for regulating IL-17A protein production that might be relevant to other cytokines, and highlight the need to consider non-canonical roles of signaling intermediaries in the immune system. Read the story in Revu et al, Science Signaling 2023

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IL-17 dependent fibroblastic reticular cell training boosts host-protective immunity to mucosal infection through IL-10 producing B cells

We show that non-specific gut inflammation (DSS colitis) activates gut-draining LN, leading to long-lasting improvement of the B cell response to a subsequent Citrobacter rodentium infection. Surprisingly, IL-17-mediated activation of LN stromal cells reduced gut inflammation, by increasing tissue production of IL-10 by B cells. We propose that this is a new form of immune training through inflammatory activation of stromal cells in local lymph nodes. Read the story in Wu et al, Science Immunology.

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IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival

We found that IL-17 is important for successful proliferation of fibroblastic reticular cells (FRC) (Majumder et al, Nature Immunology 2019). FRC are structural regulators of immune cells in LN, and we showed Th17 cells promote FRC metabolic reprogramming through IL-17. While IL-17 was known to drive inflammation, this study uncovered a new function for IL-17 in altering metabolic fitness that has since been shown to play roles in wound healing and cancer-associated fibroblasts. We are now investigating the underlying signaling pathways for metabolic reprogramming by IL-17, and the functional consequences on adaptive immunity.  

Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen

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STAT3 is a signal transducer downstream of early and late Th17-promoting cytokines like IL-6 and IL-23. Since STAT3 is required for initial Th17 development, we set up a system where Th17 cells would develop and then delete STAT3 by crossing IL-17cre with STAT3fl/fl. This showed that STAT3 is important for effector Th17 functions by maintaining mitochondrial membrane potential and the capacity of effector Th17 cells to respond to antigen stimulation. Read the story in Poholek and Raphael et al, Journal of Experimental Medicine.

IL-23 and IL-1b drive human Th17 cell differentiation and metabolic reprogramming in absence of CD28 costimulation

CD28 is considered a critical signal 2 for T cell activation, but surprisingly addition of CD28 inhibited human Th17 cell development in a dose-dependent manner. We propose that TCR/CD28 mediated activation of Akt tunes Th17 development in a Goldilocks model. Since one of the major functions of CD28 is to boost the metabolic activity of activated T cells, we investigated whether Th17-promoting cytokines IL-23 and IL-1b affect this function, again suggesting that Th17 cells thrive under conditions that promote intermediate metabolic activity. Read more about the phenotype of these cells in our Cell Reports paper.  

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