Targeting Follicular Helper T cell Metabolism in Lupus
Follicular T cells are harmful in lupus because they spur other immune cells to release damaging proteins called antibodies. We have identified several metabolic differences between follicular T cells and other immune cells. Mitochondria, the structures that provide power for cells, are more active in follicular T cells, for instance. We now plan to test mice to find out whether these differences are crucial for follicular T cells to function. We will also study mice that are missing key enzymes for metabolism to find out if they have less severe lupus symptoms.
What this study means to people with lupus
“Immune cells known as follicular T cells may be one of the main culprits in lupus. We have found that these cells have a distinctive metabolism. Our new work will try to discover whether the cells’ unique metabolism promotes development of lupus and whether targeting it is a possible approach for new treatments.”
Systemic lupus erythematosus (SLE), or lupus, is a systemic autoimmune disease characterized by loss of tolerance to cellular components and excessive production of autoantibodies. Emerging studies highlight a key population of T cells in this process: T follicular helper (Tfh) cells, which reside in germinal centers (GCs) and promote B cell function and T cell-dependent antibody responses. While recent studies have identified important immune receptors (e.g. ICOS) and transcription factors (e.g. Bcl6) for Tfh differentiation, how signals are transduced from receptors to transcriptional and biological responses remains poorly defined. Emerging studies highlight the key roles of metabolic reprogramming in coordinating effector T cell fate decisions. CD4 T cells of SLE patients and mouse models of lupus present metabolic alterations, including dysregulated mTOR complex 1 (mTORC1) activity, glycolysis and oxidative metabolism. We have shown that Tfh cells exhibit unique metabolic features, and targeting glucose metabolism and mTOR signaling dampens Tfh and GC responses. However, while the role of glucose metabolism or glycolysis is relatively well appreciated in T cell biology, we have very limited information on the extent to which T cell responses are regulated by other metabolic pathways. Moreover, whether and how metabolic programs intersect with immune signals are unclear. The goal of this application is to identify, at the fundamental and mechanistic levels, novel metabolic pathways and their interplay with immune signals in the contexts of Tfh differentiation and lupus pathogenesis. Our central hypothesis is that metabolic pathways and their intersection with immune signals orchestrate Tfh responses and represent novel targets for lupus therapy. Aim 1 will establish metabolic control of Tfh responses and lupus development. Aim 2 will establish signaling and metabolic basis that underlies Tfh responses and lupus pathogenesis. Our studies should reveal novel mechanisms and key steps in the pathogenesis of lupus and promise to establish innovative therapeutic targets.