MicroRNA‐142 controls thymocyte proliferation

Abstract

T-cell development is a spatially and temporally regulated process, orchestrated by well-defined contributions of transcription factors and cytokines. Here, we identify the noncoding RNA miR-142 as an additional regulatory layer within murine thymocyte development and proliferation. MiR-142 deficiency impairs the expression of cell cycle-promoting genes in mature mouse thymocytes and early progenitors, accompanied with increased levels of cyclin-dependent kinase inhibitor 1B (Cdkn1b, also known as p27 ). By using CRISPR/Cas9 technology to delete the miR-142-3p recognition element in the 3'UTR of cdkn1b, we confirm that this gene is a novel target of miR-142-3p in vivo. Increased Cdkn1b protein expression alone however was insufficient to cause proliferation defects in thymocytes, indicating the existence of additional critical miR-142 targets. Collectively, we establish a key role for miR-142 in the control of early and mature thymocyte proliferation, demonstrating the multifaceted role of a single miRNA on several target genes.

Control of Immunoregulatory Molecules by miRNAs in T Cell Activation

“…Conversely, other miRNAs boost the immune response. For instance, miR-142-deficient mouse T cells showed reduced proliferation, deregulated cytokine expression and decreased secretion of pro-inflammatory cytokines such as IFN-γ, IL-17, and IL2 in response to activation ( 32 , 33 ). Other examples of enhancer miRNAs are miR-155 and miR-17~92; miR-155-depleted mice are immunodeficient ( 34 ), whereas miR-17~92-deficient T cells exhibited reduced antitumoral responses ( 35 ).…”

MicroRNA in T-Cell Development and T-Cell Mediated Acute Graft-Versus-Host Disease

“…For instance, some, but not all, functions of miR-155 in the immune system could be ascribed to its repression of Socs-1 ( 47 ). On the other hand, targeted deletion of a miR-142-binding site in Cdkn1b did not phenocopy aberrant proliferation of thymocytes observed in miR-142-deficient mice ( 48 ).…”

“…A cluster of six related miRNAs, miR-17–92, confers competitive fitness to the earliest T-cell progenitors in the thymus and pre-thymic progenitors by regulating IL-7 receptor levels and IL-7 signaling ( 85 ). Conversely, miR-142 curtails numbers of early T-lineage progenitors, although loss of this miRNA inhibits proliferation and ultimately results in peripheral lymphopenia ( 48 ). Together, miR-17–92 and miR-142 help to explain the majority of T-lineage developmental defects observed upon early depletion of all miRNAs.…”

“…Once outside the thymus miRNAs are critical for peripheral maintenance and proliferation of T cells. Thus, T cells deficient in miR-142 fail to expand after egress from the thymus and do not efficiently proliferate upon TCR triggering ( 48 , 61 ). Similarly, T cells lacking miR-17–92 proliferate inefficiently after stimulation in vitro and after infection, a defect that can be partially restored by re-introduction of miR-17 and miR-92a ( 62 , 63 , 82 ).…”

Functional Role of MicroRNAs in Thymocyte Development

“…For instance, miR-142 is an evolutionarily conserved miRNA that can be selectively expressed in hematopoietic tissue. Mildner et al [44] showed that the deletion of miR-142 could affect cell homeostasis. Their further analysis revealed that miR-142 was required for thymocyte precursor development and T-cell maturation.…”