Ylva Successfully Defends Her Master Thesis!
Ylva Carlen has successfully defended her master thesis. You can find her summary below.
Determination of the role of T-bet in regulatory T cells during type 1 immune response
Tregs suppress the immune response to prevent autoimmunity and limit immune pathology but also compromise anti-tumor immune response or prevent pathogen clearance during chronic viral infections. During a type 1 immune response, Tregs acquire a specific specializa-tion, which is defined by the upregulation of specific co-inhibitory receptors, transcription fac-tors and chemokine receptors. Since T-bet is defined as master regulator for Th1 development and function, and T-bet in Tregs was shown to be essential in controlling Th1 response, we aimed to determine the role of T-bet in Tregs during type 1 immune response. We demon-strate that T-bet KO Tregs display an impaired specialization indicated by the reduced expres-sion of co-inhibitory receptors. The analysis of heterozygous Foxp3-Cre-/+xTbx21fl/fl and homo-zygous Foxp3-Cre+/+xTbx21fl/fl mice revelated that the impaired specialization of Tregs differs, depending on the environment by which the Tregs are surrounded. T-bet KO Tregs in a WT-like environment display a reduced expression of Lag-3, Tim-3, TIGIT, CD85k and PD-1. Tregs in homozygous Foxp3-Cre+/+xTbx21fl/fl mice experience a more inflammatory environment, as T-bet KO Tregs are less suppressive and consequently the immune system more activated. These T-bet KO Tregs have a reduced expression of Lag-3 and Tim-3 while the expression of CD85k and PD-1 is elevated. The impaired specialization of T-bet KO Tregs leads to a reduced suppres-sive capacity. Taken together, our results demonstrate that T-bet contributes to the expression of each of these co-inhibitory receptors in Tregs and indicate that other transcription factors and cytokines are also involved in their expression. Secondly, we investigated the influence of these less suppressive Tregs on the formation of memory CD8+ T cells and CD8+ T cell exhaus-tion. T-bet KO Tregs don’t alter the formation of memory CD8+ cells but they partially rescue CD8+ T cells form terminal exhaustion. Homozygous Foxp3-Cre+/+xTbx21fl/fl mice harbour higher levels of Texprog, Texeff, and Texinter but less CD8+ T cells were in the terminally exhausted Texterm state. How T-bet KO Tregs interfere with this differentiation trajectory can at this point only be speculated and requires further studies. To conclude, T-bet plays an important role for Treg phenotypic specialization and function during a Type 1 immune response.
