Interleukin-2 dependent STAT5 activation drives regulatory T cell development

Appropriate control of the immune system is required not only for an effective response to infectious challenges, but also required to maintain tolerance to self-antigens. Recent murine and human research has indicated that a subset of CD4+ T lymphocytes, named regulatory T cells (Tregs), are involved in controlling immune responses to infectious agents, as well as to self-antigens. However, the molecular factors that influence the development of Tregs have remained elusive. In this thesis we specifically examined the role of Interleukin-2 receptor (IL2R) signaling in the development of Tregs. Herein, we demonstrate that a deficiency in IL2R signaling dramatically reduces Treg development. Furthermore, IL2Rbeta-chain-dependent cytokines IL2 and IL15 act in a redundant manner to promote Treg development. Thus, IL2R stimulation is critical for Treg development.; To examine the signaling pathways downstream of the IL2R that promote Treg development, we utilized mice expressing a constitutively active form of the transcription factor STAT5 (STAT5b-CA). Initial analysis of STAT5b-CA mice demonstrated that constitutive activation of STAT5 results in an expanded population of Tregs in both the thymus and peripheral lymphoid organs. Furthermore, the constitutive activation of STAT5 is able to rescue Treg development in the absence of all other IL2R-dependent signals. These findings identify STAT5 as a key intracellular mediator of Treg development.; Finally, we find that STAT5 drives Treg lineage commitment by acting in a coordinated signaling pathway with T cell receptor (TCR) stimulation. Specifically, we find that constitutive activation of STAT5 is able to drive T cell progenitors into the Treg lineage, independent of their TCR specificity. Furthermore, we demonstrate that STAT5 can bind to the promoter of the Treg lineage specification factor foxp3 in Tregs, suggesting that STAT5 is able to drive Treg lineage commitment by effecting the transcription of foxp3. Based on the findings reported in this thesis, we propose that Treg development is programmed in the thymus by TCR-dependent induction of IL2 responsiveness and subsequent STAT5 activation. These findings identify STAT5 as a potential therapeutic target to manipulate Treg development in individuals with disorders resulting from ineffective Treg activity.