|Ph.D Student||Barsheshet Yiftah|
|Subject||The Role of CCL1 in the Potentiation of Foxp3+ Regulatory|
CD4+ T Cells
|Department||Department of Medicine||Supervisor||Professor Nathan Karin|
|Full Thesis text|
Regulation of T cells peripheral tolerance is mediated by two populations of regulatory T cells (Treg), CD4Foxp3 Treg cells and those that are CD4FOXP3- T regulatory-1 cells (Tr1) which produce large amounts of IL-10 in response to their target antigen. Both are thought to participate in the regulation of inflammatory responses and in the context of autoimmune diseases. Chemokines are small (~8-14 kDa), secreted proteins, structurally similar to cytokines, that regulate cell trafficking through interactions with a subset of seven-transmembrane G protein-coupled receptors (GPCRs ( . Most of the attention has been devoted to understanding their activities as pro-inflammatory mediators that direct the migration of inflammatory monocytes from the bone marrow to the inflammatory site. Chemokines also control the migration of CD4 T cells to inflammation and recently discovered to polarize them to become highly potent effector T cells, making them, and their receptors, classical targets for therapeutic interventions in inflammatory autoimmune diseases. The current study focuses on identifying the reciprocal chemokine that potentiates the biological function of CD4Foxp3 Treg cells. We show that of the different chemokines to which FOXP3 T cells possess receptors for, the chemokine CCL1 preferentially potentiates the suppressive function of these cells. It does so, in part, by increasing the expression of three molecules that play a major role in executing the suppressive function of FOXP3 Tregs. [p1] CCL1 binds a single receptor named CCR8. We show that this chemokine is preferentially transcribed at the site of inflammation within the CNS by CD4 T cells and preferentially by FOXP3 T cells at this site. This implies for a regulatory positive autocrine effect. This chemokine, and all other chemokines that we tested, could not shift the polarization of FOXP3- to FOXP3 induced Tregs (iTregs), as does transforming growth factor beta (TGF-b), and could neither synergize with TGF-b on polarizing these cells. Yet when administered (as a fusion protein) during ongoing EAE, CCL1 could rapidly suppress an ongoing disease while increasing the suppressive function of Foxp3 Tregs. The mechanistic basis underlying these results found to be dependent on the up-regulation of 3 main regulatory molecules expressed by Treg named CD39, Granzyme-B and the regulatory cytokine IL-10. These molecules are up-regulated via the phosphorylation of STAT-3 transcription factor which is crucial for Treg suppressive function.