miRNA-mediated regulation of T cell plasticity

CD4+ T helper (Th) lymphocytes are key players in coordinating effective immune responses against infiltrating pathogens. Based on cues in their microenvironment, Th cells differentiate into subsets with specific functions that shape immune responses in order to neutralize infections. Initially conceived as fixed subsets, we and others have found that Th cells demonstrate a substantial level of plasticity. This plasticity was shown to participate in diverse immune responses. We have identified the inductive switches that trigger reprogramming of Th2 cells towards hybrid Th2+1 cells following viral infection. The process requires the concerted action of T cell receptor stimulation, type I and type II interferon and interleukin-12 signals, as well as the transcription factor T-bet. This reprogramming was essential to circumvent irrepressible viral replication and fatal immunopathology. Unfortunately, a detailed understanding of the engaged molecular mechanisms is still missing. The goal of this study is to address the influence of post-transcriptional regulation on the manifestation of T cell plasticity and function. A microRNA array analysis of classically defined Th1 and Th2 cell subsets in comparison to Th2+1 cells unraveled a small panel of miRNAs that are highly and preferentially expressed in hybrid cells. This finding along with reports that demonstrate the importance of miRNAs regulating lymphocyte differentiation and function prompted us to address the implication of miRNAs in the process of T cell reprogramming. So far, we have gathered data that strongly indicate that type I interferons (IFN-a/ß) are responsible for the miRNA expression profile of Th2+1 cells. Most abundantly, microRNA-7a (miR-7a) is induced that was recently described in cancer cells to be essential for the modulation of metabolism by targeting the PI3K/Akt/mTOR signalling cascade. Latest findings dealing with the regulation of metabolism in T cells revealed the importance of mTOR signalling on T cell differentiation. By this means, we hypothesize that miR-7a may not only be implicated in the reprogramming of Th2 cells, but may also contribute to a general, priory unappreciated, mechanism of type I interferon action on immune cells to modulate their metabolic activity during times of infection. Thus, my project contributes to the understanding of post-transcriptional modulation of Th cell differentiation and addresses the novel aspect of miRNA-mediated fine-tuning of metabolism in the course of type I interferon signalling. This is of paramount importance for the further understanding of T cell-dependent immune responses in general as well as for the improvement of immunological therapies since type I interferons offer major clinical applications to treat diseases such as cancer, viral hepatitis and multiple sclerosis.