Oral Presentation Melbourne Immunotherapy Network Winter Retreat 2018

TCF-1 Critically Regulates CD8+T cell Fate and IL-17 Production (#26)

Lisa Mielke 1 , Yang Liao 2 , Matthew Firth 2 , Ella Bridie Celmens 3 , Brigette Duckworth 2 , Qiutong Huang 2 , Francisca Almeida 2 , Michael Chopin 2 , Tracy Putoczki 2 , Philip Hodgkin 2 , Hai-Hui Xue 4 , Vanessa Bryant 2 , Katherine Kedzierska 3 , Wei Shi 2 , Gabrielle Belz 2
  1. School of Cancer Medicine, Olivia Newton-John Cancer Research Institute and La Trobe University, Heidelberg, Victoria, Australia
  2. Walter and Eliza Hall Institute, Parkville, Vic, Australia
  3. Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  4. Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA

Interleukin-17 (IL-17)-producing T cells are associated with rapid progression of colorectal cancer (CRC) and poor patient survival. Recent reports have linked the development of IL-17 producing T cells with our microbiome and separate studies have established a role for the microbiota in response to checkpoint blockade in cancer patients. Therefore, the study of these cell populations in cancer is now of particular relevance. The transcriptional networks controlling the differentiation of IL-17 producing cells, including IL-17-producing CD8+ T (Tc17) cells is unknown. We show that the transcription factor TCF-1 acts to limit Tc17 differentiation in developing CD8+T cells by binding to the promoter regions of Maf, Rorc and Sox13 to suppress their expression. TCF-1 dually acted to induce genomic accessibility of key genes associated with the differentiation and the function of effector and memory CD8+T cells, but also limited the genomic accessibility of key genes essential for Tc17 cell differentiation and function. Tc17 cells exhibited a gene-set signature enriched for tissue repair and lipid metabolism, which is in sharp contrast to the transcriptional profile governing effector CD8+T cells. Collectively, these findings identify new regulators of Tc17 cells and highlight a critical role for TCF-1 in determining CD8+T cell fate through regulation of the MAF-RORgt-SOX13 axis.