Determinants of follicular helper T cell expansion in lupus

University Of Texas Hlth Science Center, San Antonio TX

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) is a complex autoinflammatory disease in which derailed follicular T helper (Tfh) cells promote autoreactive B cells producing antinuclear autoantibodies implicated in the pathogenesis of SLE. Thus, efforts to primarily program the metabolism of Tfh cells are of considerable interest to limit autoantibody and alleviate the progression of lupus. We demonstrate that oral treatment with 2-deoxy-D-glucose (2DG) integrates transcriptomic and metabolic signaling to synergistically limit glycolysis, resulting in peripherally control of Tfh cells and significantly ameliorating lupus in mice. Furthermore, TEPP-46, which stabilizes tetrameric pyruvate kinase muscle isozyme 2 (PKM2) and prevents its nuclear translocation, also programs the transcriptomes of ileal epithelial cells (iECs) and Peyer’s patch (PP) B cells and reduces autoantibodies in lupus mice. The objective of this research proposal is to further clarify the pharmacological effect of TEPP-46 compared to 2DG, which restricts the metabolic circuits of intestinal cell complexes, particularly iECs that continuously interact with the gut microbiome and physiologically support PP microenvironment. This contributes to restrictive glycolysis in PP Tfh cells and critically limits the local B cell repertoire (e.g., IgA+ B cells) that support the microbial taxa and regulate peripheral autoantibody, thereby synergistically ameliorating lupus in mice. Our hypothesis is that TEPP-46-limiting glycolytic metabolism, like 2DG, physiologically rewires iECs to locally support the programming of PP Tfh cells that regulate B cells to tightly control the gut microbiome and peripheral autoreactive B cells, thereby mitigating the disease in the host. The specific aims are: 1. Elucidate the effects of TEPP-46 compared to 2DG on iECs and the gut microbiome in lupus mice. 2. Delineate the glycolytic regulation in locally programming Tfh cells of lupus mice orally treated with TEPP-46 compared to 2DG. And 3. Investigate the pharmacological control of local and peripheral B cells synergistically ameliorating lupus in mice. The expected results will be the first detailed report of a compound-dependent therapeutic intervention programming key glycolytic pathways (e.g., PKM2) that physiologically control the ileal epithelium and host microbiome to support autoantibody-limiting Tfh cells, thereby effectively ameliorating the disease in mice.