ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

JAZF1 shapes the metabolic landscape of human Treg (#234)

Kate L Shepherdson 1 , Cheryl Y Brown 1 , Holly A Withers 1 , Christopher M Hope 1 , Simon C Barry 1
  1. Robinson Research Institute, The University of Adelaide, North Adelaide, South Australia, Australia

Regulatory T cells (Treg) play a vital role in promoting immune tolerance and helping to protect against autoimmune diseases. FOXP3 is the master transcription factor of Treg and is essential for their formation and function. It is proposed that dysregulation in the Treg FOXP3 controlled gene network is a significant component of autoimmune diseases. The Barry lab has mapped human Treg gene expression, revealing the genes that are direct targets of FOXP31. The transcription factor JAZF1 was identified by Barry lab as being upregulated by FOXP3 in Treg. Importantly, the JAZF1 locus contains genetic risk SNPs for multiple autoimmune diseases, including IBD, SLE, psoriasis, and systemic sclerosis2,3,4,5,6,7. However, the exact role of JAZF1 in Treg has yet to be uncovered.

This project tested the hypothesis that JAZF1 is required by Treg to reinforce their functional phenotype. CRISPR/Cas9 technology was utilised to generate donor matched JAZF1 knock out (KO) and control Treg populations. qRTPCR was used to investigate the targets of JAZF1, including metabolism associated and Treg signature genes. in vitro metabolism and suppressor assays were undertaken to investigate alteration to the metabolic fitness and suppressive capabilities of JAZF1 KO Treg.

Results from these experiments suggest that JAZF1 may regulate key glycolysis and TCA cycle associated genes. JAZF1 KO Treg had increased expression of glucose transporters: GLUT1 and GLUT3, glycolysis related genes: HIF1a, STK11, HK2 and ENO1, and proliferation associated genes: cMyc and RPTOR. There were also changes in TCA cycle associated genes: IDH1, MDH1 and ACO2. JAZF1 KO Treg maintained their overall suppressive capabilities during in vitro suppressor assays and the expression of Treg signature genes: IL-10, CTLA4 and FOXP3 were either upregulated or unchanged in the JAZF1 KO Treg. Overall, these results suggest that JAZF1 may have an important role in maintaining the metabolic fitness of Treg.

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