Transcriptional Regulation in Murine Regulatory T Cells and Suppressed CD4+ T Cells: Identification and Functional Analyses

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The maintenance of peripheral tolerance is largely based on CD4+FoxP3+ Thymus-derived regulatory T cells (Tregs). While on the one hand preventing the development of autoimmune and allergic diseases, Tregs contribute to cancer pathogenesis and progression. Therefore, the in vivo modulation of Treg-derived suppressive mechanisms is a worthwhile but challenging task. This can be achieved by either targeting the suppressive properties of Tregs directly or by rendering the responder cells, e.g. CD4+ T cells resistant to Treg-mediated suppression. However, the molecular principles of suppression still remain relatively obscure. Our analyses clearly revealed an important role of cAMP in Treg-mediated suppression. Coherently, we observed a strong induction and nuclear localization of the transcription factor Inducible cAMP Early Repressor (ICER) in suppressed CD4+ T cells in vitro as well as in vivo. CD4+ T cells from Icer-deficient mice revealed a strongly reduced susceptibility to Treg-mediated suppression in vitro. In addition, such mice are less susceptible in a B16F10 melanoma model indicating a reduced sensitivity of Icer-deficient T cells to Treg-mediated suppression.Since kinases strongly influence transcriptional regulation, we performed kinome analysis comparing conventional CD4+ T cells and Tregs. Casein kinase 2 (CK2) showed the highest activity in activated Tregs. Pharmacologic inhibition in vitro as well as genetic ablation of the beta subunit of CK2 specifically in Tregs demonstrated a crucial contribution of this kinase to the suppressive properties of Tregs. Hence, this project focuses on 1. the analysis of the molecular mechanisms steered by ICER in suppressed CD4+ T cells, 2. the downstream signaling events evoked by CK2 in Tregs contributing to their suppressive properties as well as 3. the interrelation of CK2 and cAMP-mediated induction of ICER.