The role of Ikaros in Foxo1-driven gene expression in CD4 T cells
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The existence of a robust, mature CD4 T cell population is essential in orchestration of an immune response. CD4 T cell activation is a result of antigenic stimulation of a unique cell pool that is normally resting. Termed “naïve”, these CD4 T cells lack effector function and are maintained long term in the periphery. Expression of key cell surface receptors and transcription factors dictates their ability to survive, home and differentiate into effector subsets. However, transcriptional regulation of these processes in naïve CD4 T cells is only partly characterized. Ikaros has been identified as a transcriptional activator and repressor of T cell lineage fate decisions and polarization into T helper cell subsets. In this dissertation, a role for Ikaros in regulation of naïve CD4 T cells is revealed as in its absence, cells exhibit decreased survivability, impaired migration to lymph nodes and failure to develop into induced regulatory T cells (iTreg). Defects are linked to decreased expression of IL- 7Rα, CD62L and Foxp3, respectively, all identified as targets of a transcription factor important in naïve CD4 T cell homeostasis, Foxo1. Analogous consequences on T cell survival, homing and differentiation have been reported for Foxo1- deficient T cells. Furthermore, results from Western blot and qRT-PCR analyses of protein and mRNA from Ikaros null (IK-/-) CD4 T cells demonstrated decreased Foxo1 levels, prompting investigation into mechanisms for regulation of Foxo1 expression by Ikaros. Retroviral transductions were performed, beginning with delivery of Ik-7 and Foxo1-shRNA, interfering with Ikaros and Foxo1 activity in wild type cells, respectively. Similar decreases in CD62L and IL-7Rα levels indicated the need for both Ikaros and Foxo1 for expression. However, re-introduction of either Foxo1 or Ikaros into IK-/- CD4 T cells highlighted differential modes of Ikaros and Foxo1 regulation for IL-7Rα and CD62L expression. qRT-PCR analyses revealed increased levels of Foxo1 mRNA with Ikaros transduction into IK-/- CD4 T cells. My studies have thereby identified Ikaros to be the first transcriptional regulator of Foxo1 gene expression in ensuring survival, homing and iTreg differentiation of the naïve CD4 T cell compartment.
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