Targeting Follicular Helper CD4 T cells in SLE
A specific type of T cell drives the tissue damage that occurs in lupus. These cells need more energy than normal cells, and that might be their Achilles heel. Dr. Morel has found that the numbers of these T cells in mice can be reduced with common diabetes treatments such as metformin that deprive the cells of the sugar they need to survive. Now, her team plans to test whether these drugs can be used as a lupus therapy that will eliminate the problematic T cells.
What this study means for people with lupus
Dr. Morel and her group wants to determine whether lupus can be treated through common diabetes treatments that are used to fight against T cells.
The expansion of follicular helper CD4+ T (Tfh) cells has been recently shown to be tightly associated with disease severity in lupus patients, following multiple studies in various mouse models showing that they are necessary for the production of class-switched high-affinity pathogenic autoantibodies. We have recently published that the CD4+ T cells from lupus patients and lupus prone mice present an elevated metabolism and that treatment with metabolic inhibitors normalizes the function of these T cells in vitro and reversed disease in mice. We have obtained preliminary results showing that the frequency of Tfh cells is normalized by the inhibition of glucose metabolism in 4 mouse models of lupus, and that this targeting of Tfh cells corresponds to the elimination of autoantibodies. Remarkably, the inhibition of glucose metabolism has little effect on the production of T-dependent antibodies in response to immunization. Based on these results, we propose that Tfh cells supporting the production of autoAbs are quantitatively or qualitatively different from Tfh cells providing protective humoral immunity against pathogens. Further, we propose that targeting Tfh cellular metabolism provides an effective and safe approach to treat lupus. We propose to test this hypothesis with the three following specific aims using a combination of cellular and molecular immunology approaches in various mouse models as well as human PBLs: 1. To define the unique molecular and metabolic signatures of Tfh cells responsible for the production of autoAbs (SLE-Tfh) in lupus mice as compared to Tfh cells elicited by TD-dependent Ags (NP-OVA and VACV-OVA) in lupus and normal mice (TD-Tfh) 2. To define the responses of SLE-Tfh and TD-Tfh cells to glucose inhibition in mouse models of lupus 3. To compare the molecular and metabolic signatures of circulating cTfh cells in SLE patients (largely driven by autoAgs) to that of cTfh cells in healthy controls (largely driven by TD-Ags), as well as their response to glucose inhibition.