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.
Highlights
Upon maturation in the thymus, naïve T cells populate the peripheral lymphoid organs
Dicer ablation in T cells results in the reduction of mature CD4+ and CD8+ lymphocytes [26] suggesting that RNA interference may have a role in their maintenance
To address the question of which particular miRNAs are involved in the control of T cell homeostasis, we focused on the largest family of miRNAs, lethal-7
Summary
Upon maturation in the thymus, naïve T cells populate the peripheral lymphoid organs. Various signaling pathways are involved in the maintenance of the peripheral T cell pool. It has been well-established that a combination of homeostatic signals, such as low-affinity T cell receptor (TCR) interactions with self-peptide-MHC complexes and common gamma-chain receptor cytokines, especially IL-7, are indispensable for the prolonged survival of peripheral T cells [1,2,3]. Arginine methyltransferase PRMT5 has been recently shown to support T cell maintenance by regulating strength of signaling through common gamma-chain receptors [4]. Constant recirculation of naïve T cells through secondary lymphoid organs appears to be important for them to receive necessary homeostatic signals [5]. Control of metabolic signaling pathways is essential for T cell maintenance since deficiency in tuberous sclerosis complex 1, that restrains mTOR activity, leads
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