Functional Genomics of Tfh Cell Metabolism and Lupus Pathogenesis

Lupus is a systemic autoimmune disorder driven by overactive immune cells. An increase in the number of follicular helper T cells (Tfh) – one of the immune cell types – is associated with lupus disease activity, but how the Tfh cell increase leads to lupus progression has remained unclear.

Dr. Chi and colleagues recently discovered that Tfh cells in lupus have unique metabolism – a sum of chemical reactions taking place within each cell of a living organism that provide energy and biomass for all vital processes supporting survival – compared to other immune cells. Dr. Chi plans to use his Distinguished Innovator Award to investigate if unique metabolic features of Tfh cells are linked to and dictate their destructive behavior in lupus. Dr. Chi will also identify presently unknown factors that are involved in Tfh cell metabolism and function, which make these cells contribute to the disease activity of lupus.

What this study means for people with lupus

These studies carry promise to reveal new information about how lupus develops and progresses, which may help identify innovative therapeutic targets for future lupus treatments.

T follicular helper (Tfh) cells, which promote B cell functions and antibody responses, play a key role for the pathogenesis of systemic lupus erythematosus (SLE), or lupus. Emerging studies highlight the central roles of metabolic reprogramming in coordinating effector T cell fate decisions including Tfh cells. We previously found that T cell subsets exhibit unique metabolic features, and inhibiting glucose metabolism or mTOR signaling dampens Tfh cells and T cell-dependent antibody responses. However, glucose metabolism and mTOR are commonly important for bioenergetic and biosynthetic demands of multiple effector T cell populations, and Tfh-specific metabolic programming remains elusive. Moreover, the mechanisms linking the metabolic state of immune cells with autoimmunity are poorly understood, and in particular, integrative, systems-level understanding and therapeutic targeting of immunometabolism are lacking. The goal of our program is to investigate the interface between metabolism and immunity, and how studying immunometabolism reveals new biology and disease targets for lupus. We approach these questions by integrating hypothesis-driven and systems immunology approaches, including pooled in vivo CRISPR screening, in-house development of data-driven network algorithms NetBID and scMINER, and systems proteomics, which led to new concepts, ‘hidden drivers’ for immunometabolism, and therapeutic targets that cannot be surmised from simpler systems. In particular, through in vivo CRISPR screening, we found that phospholipid metabolism via phosphatidylethanolamine (PE) selectively coordinates Tfh responses and humoral immunity (Nature 2021), highlighting metabolic controls of context-dependent immune effector programs that promise to establish innovative therapeutic targets for autoimmunity. Our central hypothesis is that metabolic pathways are inextricably connected to T cell immunity and autoimmune diseases, and therefore, by understanding these connections, we gain new concepts and disease targets. The specific aims of this proposal are to explore both candidate (phospholipid metabolism) and systems (in vivo CRISPR screening) approaches to establish Tfh cell biology and heterogeneity and reveal new targets for lupus. Aim 1 will target PE metabolism for Tfh responses and lupus pathogenesis. Specifically, we will establish mechanisms for selective phospholipid metabolism in Tfh cells, and genetically define and chemically target PE synthetic pathway for lupus therapy. Aim 2 will establish metabolic heterogeneity and hidden drivers of Tfh responses. Specifically, we will identify cellular heterogeneity and hidden drivers in autoreactive Tfh cells from lupus-prone mice and circulating Tfh-like cells from SLE patients, and apply pooled, single-cell and spatial CRISPR screening to reveal functional drivers and heterogeneity of Tfh cells. Our inter-disciplinary studies promise to establish fundamental mechanisms and innovative targets for lupus.