Defining the let-7 microRNA-mediated molecular mechanisms regulating T cell differentiation

CD4+ and CD8+ T cells are lymphocytes of the adaptive immune system that play essential roles in immunity. Both T cell subsets recognize their cognate antigen through the T cell receptor (TCR), which induces the proliferation and differentiation of these antigen-specific cells into effector T cells. CD4+ T cells have the potential to differentiate into one of multiple lineages of helper T (Th) cells and participate indirectly in antigen clearance by orchestrating the function of other cells. CD8+ T cells differentiate into cytotoxic T lymphocytes (CTL), which directly contributes to the resolution of an infection by killing cancerous or virally-infected cells. Upon antigen clearance, most effector T cells die, but some survive and generate long-lived memory T cells that will respond faster and more efficiently to subsequent encounters with the same antigen. When antigen fails to be cleared, such as in chronic infections and cancer, effector T cells are diverted into a hyporesponsive state, exhaustion, characterized by the upregulation of co-inhibitory receptors that transmits inhibitory signals resulting in the loss of effector function and memory potential. Moreover, when T cell differentiation is dysregulated, T cell responses become aberrant, causing autoimmune diseases. Therefore, understanding the molecular mechanisms controlling T cell responses is important to develop innovative treatments that can enhance T cell activity during infections and cancer, and dampen the generation of disease-causing T cells in autoimmunity. We have uncovered a novel post-transcriptional mechanism regulating T cell differentiation. Particularly, we showed that the let-7 family of miRNAs is highly expressed in naive T cells, but gets dramatically downregulated upon antigen encounter, proportionally to both the strength and duration of TCR stimulation. Specifically, let-7 downregulation was required for the differentiation of pathogenic Th17 cells in experimental autoimmune encephalomyelitis (EAE), a mouse model of the autoimmune disease multiple sclerosis (MS). In CD8+ T cells, although let-7 inhibits CTL differentiation in vitro, let-7 was demonstrated both in silico and in vivo to promote memory CD8+ T cell formation, while repressing the differentiation of terminal effectors, which are susceptible to exhaustion. Thus, let-7 constitutes a promising tool for the therapeutic manipulation of T cell responses