SUMMARY Optimal immune regulation is essential at the mucosal epithelium of the intestine that separates the antigen- rich gut lumen from the sterile inner core of the body. In addition to forming a physical barrier, the epithelium also carries out vital digestive functions and any tissue damage, induced by invading pathogens or excessive inflammation can jeopardize the integrity of this critical border. Consequently, the mucosal immune system is faced with the unique challenge to provide optimal and immediate protection but also to do so with the least damage to the tissue. This dilemma imposes a constant pressure for the immune cells to adjust their immune function in a way that is compatible with a defensive role able to protect the mucosal border but not destroy it. This is especially an issue for CD4 T helper (Th) cells, which have the potential to differentiate to Treg and suppress protective immune responses or to inflammatory effector cells like the Th17 cells that can initiate excessive inflammation and induce severe immune pathology. Recently, we discovered that mature CD4 T cells that migrate to the intestinal epithelium adapt to the environment by functionally divert from their suppressive or inflammatory Th fate but instead reprogram to become protective CD8-like cytotoxic effector cells. The reprogramming of CD4 cells to cytotoxic T lymphocytes (CTL) is a critical process that adapts them to the mucosal environment and defects in the reprogramming process lead to the generation of highly inflammatory Th17 T cells that cause severe tissue destruction in the intestine. Although extremely important, nothing is known about the molecular mechanism or factors that drive the reprogramming process in mature CD4 T cells. Preliminary studies however lead to the discovery of a novel long non-coding RNA(LncRNA), which we have called, Switch, because we found that it is uniquely expressed in CD4 CTL precursor cells but more importantly because its expression directly associates with the switching-on of the Runx3-dependent CTL gene transcription program and the switching-off of the RORγt- and Foxp3-controlled CD4 Th fates in in vitro- and in vivo-activated mature CD4 T cells. In addition, we found that loss-of-function of Switch impaired the reprogramming of CD4 Th cells to CTL and led to the accumulation of highly pathogenic Th17 T cells in the intestine. These observations support a role for Switch as a “master regulator” of CD4 plasticity as well as a critical controller of the mechanism to adapt the functional fate of mucosal CD4 T cells in a way that is compatible with the unique challenges at the mucosal interface of the intestine. We propose here to elucidate the molecular mechanisms by which this novel LncRNA, Switch, is able to function as a central hub for CD4 T cell plasticity that stretches beyond the Th fates and re-directs mature CD4 T cells to the Runx3-controlled CTL lineage fate while suppressing the alternative pathways that lea...