Th17 cells orchestrate inflammation and immunoregulation
Our interests revolve around understanding the diverse and sometimes enigmatic roles of IL-17 in directing both pathogenic and protective outcomes following infection, injury or autoimmune activation.
Th17 cell differentiation: unique signaling pathways and mechanisms
Naïve T cells receive multiple signals that drive them to proliferate and change their function. 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 that CD28 costimulation is inhibitory for human Th17 cell development, through pAkt activation, that tunes Th17 cell activation (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 compensate for some of the functions usually provided by CD28, including increased glucose uptake and glycolytic capacity.
Ongoing work in our lab is now focused on understanding how CD28 and other signaling pathways modulate the Th17 program in both mouse models and human T cells. For example, we examined one of the regulators of Akt activation, PIP2, and discovered that it is present in high concentrations in the nucleus of Th17 cells, leading us to find an unexpected role for PIP2 in IL17A translation (Revu et al, Sci Signaling in revision). There are some key differences between mouse and human CD28 signaling, as demonstrated by the disastrous clinical trial for CD28 superagonist, where severe cytokine storm was not predicted by preclinical models. To make our studies more physiological, we are testing the effects of blocking these pathways in effector Th17 cells in myelin-activated Th17 cells from blood of people with multiple sclerosis, in collaboration with Dr Xia at University of Pittsburgh. 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 beneficial versus autoimmune Th17 induction (and T cell activation in general) in vivo in a relevant system.
Fibroblastic Reticular Cells as Targets of IL-17 to regulate adaptive immunity
In secondary lymphoid organs, stromal cells called FRC help organize the lymph node by producing chemokines and survival cytokines for lymphocytes (e.g. CCL19 and IL-7 for FRC in the T cell zones). FRC help regulate the adaptive immune response by inhibiting Th1 cells, deleting self-reactive T cells and promoting Tregs. On the other hand, loss or dysfunction of FRC causes reduced lymphocyte viability and impaired immune responses to viruses. 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). A follow-on study showed that prior activation of FRC by IL-17 conditioned the LN such that future responses to a gut infection were less inflammatory (less symptomatic) and had improved B cell responses (Wu et al, Science Immunology 2021).
We have several current projects relating to IL-17 and FRC. We are working to understand molecular mechanisms governing metabolic reprograming and IL-17 mediated functions of FRC, using in vivo models with FRC-specific knockdown of IL-17 signaling intermediates. We are investigating IL-17-dependent immune training of FRC in additional models of infection and autoiommunity to understand consequences for adaptive immunity, especially development of regulatory B cells as a mechanism to control symptom severity. Understanding how IL-17 promotes B cell and antibody production through FRC has implications for vaccine design as well as autoimmune patient populations receiving IL-17 blockers. Finally, we have uncovered a surprising IL-17:FRC axis that regulates severe immunopathology and T cell exhaustion during chronic viral infection and are working to understand roles of IL-17 in balancing host-protective antiviral responses.