Role of regulatory T cells in the development and progression of chroniclymphocytic leukemia

Regulatory T cells (Treg) represent a subtype of CD4 + CD25 + T cells withimmunosuppressive capabilities. Mainly involved in immune tolerance, Tregcontrol the functions of effector T cells but also antigen presenting cells, inparticular by the secretion of cytokines. The roles of Treg in cancers aremultiple. Our recent study showed an increase in the percentage of Treg indiseased Eμ-TCL1 mice and a strongly immunosuppressive activatedphenotype (Wierz et al., Blood, in revision). Interleukin (IL-) 35 contributesto and is necessary for induction of Treg but is also produced by Treg toperform their immunosuppressive function. Recent studies have also showna strong expression of AHR and HIF-1α transcription factors in activatedTreg.The aim of this research project is to study and characterize Treg in vivo ina murine model of chronic lymphocytic leukemia (CLL) and to determine the
role of IL-35. We will develop new mouse models by crossing Eμ-TCL1(CLL model), Ebi3-/- (IL-35 deficient) and Foxp3YFP-cre mice (whose Tregexpress the fluorescent protein YFP). We will also perform adoptive transferof leukemic cells in Ebi3-/- mice. In addition, this project will make possibleto define the importance of signaling pathways dependent on thetranscription factors AHR and HIF-1α for the functions of Treg in CLL butalso in cancers more generally. To do this, we will invalidate the Ahr andHif-1a genes in Treg exclusively using the Foxp3YFP-cre mouse andAhrfx/fx or Hif1afx/fx mice. In summary, this project will help defining the role of Treg in thedevelopment and progression of CLL and in particular confirm the role ofcytokine IL-35 and of the transcription factors AHR and HIF-1α