Sphingolipid Metabolism Controls Regulatory T cell Function and Intestinal Homeostasis

PROJECT ABSTRACT
Inflammatory bowel disease (IBD) is characterized by inconsistent response to current therapies and persistent
activation of pathogenic effector CD4+ T cells, implying that regulatory T cells (Tregs) are potentially
dysfunctional. Recent evidence suggests that inflammatory-like Tregs are present in the intestinal lesions of
individuals suffering from refractory IBD; however, the underlying mechanism and its contribution to IBD are
poorly understood. Thus, the OVERALL OBJECTIVE of this proposal is to aid in the generation of more
preliminary data for a planned R01 application that will explore the molecular mechanisms by which lipid
metabolites enforce Treg phenotype and immunosuppressive function during chronic intestinal inflammation.
These insights will facilitate the development of therapeutic strategies for manipulating Tregs to treat IBD.
Untargeted metabolomics revealed that certain sphingolipids accumulate in human Tregs. This proposal
aims to then explore how these lipids are synthesized and elucidate the importance of these lipids to metabolic
homeostasis, cell signaling, and Treg function. Building on the unbiased metabolomics data, we also found that
the abundance of these lipids in Tregs can be modulated by physiologically and pathophysiologically relevant
signals. Therefore, we hope to explore the functionality of Tregs depleted of these lipids in the setting of
experimental mouse models of chronic intestinal inflammation to establish the function of these lipids in Tregs in
a manner that mirrors human IBD.
Based on these observations, we formulated the CENTRAL HYPOTHESIS that long-chain ceramides
promote metabolic homeostasis and resistance against the acquisition of effector-like phenotype in Tregs,
resulting in the preservation of immunosuppressive function. The following independent SPECIFIC AIMS are
designed to test two integrated hypotheses. First, we will directly test the hypothesis that ceramides prevent
excessive oxidation of fatty acids linked to the glycolytic-lipogenic metabolism and effector IL-17-producing T
helper (Th)17 cell-like phenotype. Furthermore, we will test the hypothesis that ceramides inhibit the activation
of the nutrient-sensing signaling pathway associated with effector type T helper (Th1) cell-like phenotype.
Second, we will test the hypothesis that Tregs depleted of ceramides exhibit poor resolution of IBD in an animal
model. We propose to utilize sophisticated approaches relevant to health and IBD pathophysiology to test our
central hypothesis. This proposal, which is technically and conceptually innovative, is also significant because
it presents a novel concept in Treg biology and identifies new mechanisms for therapeutically optimizing Tregs
to halt the refractory IBD.

Grant Number: 1R03DK139233-01A1
NIH Institute/Center: NIH
Principal Investigator: Adebowale Bamidele