Survival of Naïve T Cells Requires the Expression of Let-7 miRNAs

Abstract

Maintaining the diversity and constant numbers of naïve T cells throughout the organism's lifetime is necessary for efficient immune responses. Naïve T cell homeostasis, which consists of prolonged survival, occasional proliferation and enforcement of quiescence, is tightly regulated by multiple signaling pathways which are in turn controlled by various transcription factors. However, full understanding of the molecular mechanisms underlying the maintenance of the peripheral T cell pool has not been achieved. In the present study, we demonstrate that T cell-specific deficiency in let-7 miRNAs results in peripheral T cell lymphopenia resembling that of Dicer1 knockout mice. Deletion of let-7 leads to profound T cell apoptosis while overexpression prevents it. We further show that in the absence of let-7, T cells cannot sustain optimal levels of the pro-survival factor Bcl2 in spite of the intact IL-7 signaling, and re-expression of Bcl2 in let-7 deficient T cells completely rescues the survival defect. Thus, we have uncovered a novel let-7-dependent mechanism of post-transcriptional regulation of naïve T cell survival in vivo .

Differentiation of Pathogenic Th17 Cells Is Negatively Regulated by Let-7 MicroRNAs in a Mouse Model of Multiple Sclerosis

“…Our most striking finding is that let-7 miRNAs keep pathogenic CD4 + T cells from infiltrating the CNS. This effect was not due to a detrimental impact of let-7 miRNAs on the survival of activated CD4 + T cells, as maintenance of high let-7 miRNA expression improved the survival rate of activated CD4 + T cells, while let-7 deficiency caused an increase in cell death, which is consistent with our recently published observations in both naïve CD4 + and CD8 + T cells that let-7 miRNAs promote homeostatic survival through IL-7-independent stabilization of Bcl2 expression (29).…”

“…Interestingly, Let-7Tg cells exhibited better survival than their WT counterparts, while the recovery of Lin28Tg lymphocytes was significantly lower ( Figure 3A). In fact, these results are in agreement with our recently published findings in naïve CD4 and CD8 T cells (29), suggesting that let-7 expression also supports the survival of activated CD4 + T cells. Thus, the reduced numbers of CNS-infiltrated Let-7Tg CD4 + T cells recovered during EAE cannot be explained by increased cell death.…”

“…For instance, the upregulation of let-7 miRNAs during natural killer T (NKT) cell development in the thymus is necessary for the differentiation of IFNγ-producing effectors (27). In the periphery, let-7 miRNA expression is required for the survival and maintenance of the quiescent phenotype in naïve T cells (28,29). During lymphocyte activation, let-7 miRNAs have been shown to inhibit the metabolic reprogramming of both B cells and CD8 + T cells by negatively regulating the expression of the transcription factor c-Myc and the enzyme hexokinase 2 (28,30).…”

MicroRNA‐mediated metabolic reprogramming of chimeric antigen receptor T cells

“…It has been shown that the let-7 family is expressed in T N cells, downregulated in T EFF cells and re-expressed in T M cells. 78,79 Downregulation of the let-7 family during the expansion phase is necessary for T cell proliferation and expansion. 80 Loss of let-7 increases T cell proliferation and effector function while it also promotes differentiation of terminal effector cells, mitochondria fission and AICD in T cells.…”

“…80 Loss of let-7 increases T cell proliferation and effector function while it also promotes differentiation of terminal effector cells, mitochondria fission and AICD in T cells. 78,80 Many studies investigating the role of miRNAs in T cell function utilize murine models for infection settings. Whilst conserved miRNAs tend to have comparable targets and functions both in humans and mice, some miRNAs are divergent in both their function and targets.…”