Poster Presentation 25th Lorne Cancer Conference 2013

Differentiation and function of Foxp3+effector regulatory T cells. (#149)

Erika Cretney 1 2 , Annie Xin 1 2 , Dane Newman 1 2 , Martina Minnich 3 , Wei Shi 2 4 5 , Maria Miasari 1 2 , Frederick Masson 1 2 , Mark J Smyth 6 , Gabrielle T Belz 1 2 , Gordon Smyth 2 4 7 , Meinrad Busslinger 3 , Axel Kallies 1 2 , Stephen L Nutt 1 2
  1. Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  2. The Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
  3. Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
  4. Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  5. Department of Computer Science and Software Engineering, The University of Melbourne, Parkville, Victoria, Australia
  6. Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  7. Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia

Regulatory T (Treg) cells are required for peripheral tolerance. Evidence indicates that Treg cells can adopt specialized differentiation programs that, in addition to Foxp3, are controlled by transcription factors usually associated with helper T cell differentiation. Our group and others have previously shown that the transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) is required for the differentiation of plasma cells and short-lived CD8+ effector T cells. Here we demonstrate that Blimp-1 expression defines a distinct population of mature effector Treg cells that predominantly localize to mucosal sites and produce the anti-inflammatory cytokine interleukin-10 (IL-10). We additionally show that inflammatory signals can induce Blimp-1 expression in Treg cells. Blimp-1 was required for IL-10 production by Treg cells and for their tissue localization and homeostasis. Moreover, Blimp-1-deficient Treg cells did not adequately regulate survival proteins and chemokine receptors, ultimately leading to the accumulation and to severe functional deficiencies of these cells. We provide evidence that the transcription factor interferon regulatory factor 4 (IRF4), but not the transcription factor T-bet, is essential for Blimp-1 expression and for the differentiation of all effector Treg cells. Our recent data shows that Treg cells found within tumours express high levels of Blimp-1, have an effector phenotype with high expression of ICOS and CD103 and make large amounts of IL-10. We now wish to examine the role and function of the Blimp-1+ effector Treg subpopulation in tumour immunity. Our data have shown that IL-2 and inflammatory signals and two conserved transcription factors, IRF4 and Blimp-1, jointly regulate the differentiation, function and homeostasis of effector Treg cells. Strategies to manipulate the Blimp-1-expressing effector Treg population may prove to be effective for the treatment of autoimmune diseases, organ transplantation and cancer.