microRNAs function in CD8+T cell biology

Abstract

During an immune response, CD8(+)T cells can differentiate into multiple types of effector and memory cells that are important components of immune surveillance. However, their dysregulation has been implicated in infection with viruses or intracellular bacteria and tumorigenesis. miRNAs have been identified as crucial regulators of gene expression, and they perform this function by repressing specific target genes at the post-transcriptional level. Most miRNAs expressed in a given cell type serve the function to impede broadly cell-type-inappropriate gene expression and potently deepen a pre-existing differentiation program. It is increasingly recognized that miRNAs directly modulate the concentration of many regulatory proteins that are required for the development of immune cells in the thymus and their responses in the periphery. This review outlines our current understanding of the function of miRNAs in CD8(+)T cell biology as it impacts expression of protein-coding genes in the context of proper development, infection, as well as oncogenesis. In addition, we conclude with a perspective on future challenges and the clinical relevance of miRNA biology.

Keywords: activation; development; differentiation.

Figure 1.. miRNA-mediated regulation of CD8⁺T cell development. miRNAs have been shown to regulate multiple steps in the development of CD8⁺T cells. miR-155 targets SOCS1, Ship1, and many gene-encoded molecules that participate in type I IFN signaling and promotes CD8⁺T cell proliferation and survival. In addition, miR-155, miR-21, and miR-30b cooperate to promote CD8⁺T cell activation by repressing SOCS1, DUSP10, and BCL6, respectively. miR-181a also promotes CD8⁺T cell activation through targeting phosphatases, including DUSP5, DUSP6, PTPN22, and SHP2. In contrast, miR-146a inhibits CD8⁺T cell responsiveness through a negative-feedback loop involving the miR-146a target genes Traf6 and Irak1. Like miR-146a, miR-146b and miR-28-5p also suppress CD8⁺T cell activation, although miRNA-targeting genes in this process have yet to be identified. miR-17 ∼92 targets Pten, ID2, ID3, and BCL2 and enhances cell-cycle progression of CD8⁺T cells. miR-214 also targets Pten and promotes CD8⁺T cell proliferation. let-7b and the miR-130/301 cluster influence CD8⁺T cell migration through regulating expression of CD62-L and CD69, respectively. miR-150 and miR-223 indirectly affect CD8⁺T cell proliferation by regulating LC cross-presentation.

Figure 2.. miRNA-mediated regulation of CD8⁺T cell differentiation. In the periphery, mature CD8⁺T cell differentiation is modulated by miRNAs, including miR-17 ∼92 (targets Pten to promote expression and activation of mTOR), miR-155, and miR-21 (targets PDCD4), which promote SLECs, and miRNAs, including miR-139 [targets Eomes (early stage)], miR-342 [targets Eomes (early stage)], miR-16, miR-142-3p, miR-142-5p, miR-150 (targets CD25), miR-15b (targets DEDD), and let-7f, which promotes skewing toward memory cells (MPECs).

Figure 3.. miRNA-mediated regulation of CD8⁺T cell-effector function. During immune responses, CD8⁺T cell precursors undergo genetic remodeling that results in the expression of signature genes central to effector functions, including genes that encode T-box transcription factors T-bet and Eomes and genes associated with cytolysis. These processes are regulated by several miRNAs at distinct levels. Specifically, NF-κB signaling induces the expression of miR-155, which promotes IFN-γ production by targeting Ship1. miR-155 also indirectly promotes CD8⁺T cell production of IFN-γ by a mechanism whereby miR-155 enhances IL-12p70 production by DCs through targeting SOCS1. miR-146a, the miRNA that is up-regulated in response to NF-κB signaling, targets STAT1 and inhibits CD8⁺T cell-effector functions. miR-29 can directly target IFN-γ mRNA and decrease IFN-γ production, and its expression is inhibited by NF-κB signaling following activation. miR-17 ∼92 promotes expression of T-bet and Eomes through mechanisms that are not clear to us, which ultimately results in an increase in the production of GZMB and perforin. miR-US4-1 targets ERAP1b and thereby, interferes with the presentation of antigenic peptides to CD8⁺T cells. IFNGR, IFN-γR; ifng, IFN-γ.