Emerging Role of Non-Coding RNAs in Regulation of T-Lymphocyte Function

Abstract

T-lymphocytes (T cells) play a major role in adaptive immunity and current immune checkpoint inhibitor-based cancer treatments. The regulation of their function is complex, and in addition to cytokines, receptors and transcription factors, several non-coding RNAs (ncRNAs) have been shown to affect differentiation and function of T cells. Among these non-coding RNAs, certain small microRNAs (miRNAs) including miR-15a/16-1, miR-125b-5p, miR-99a-5p, miR-128-3p, let-7 family, miR-210, miR-182-5p, miR-181, miR-155 and miR-10a have been well recognized. Meanwhile, IFNG-AS1, lnc-ITSN1-2, lncRNA-CD160, NEAT1, MEG3, GAS5, NKILA, lnc-EGFR and PVT1 are among long non-coding RNAs (lncRNAs) that efficiently influence the function of T cells. Recent studies have underscored the effects of a number of circular RNAs, namely circ_0001806, hsa_circ_0045272, hsa_circ_0012919, hsa_circ_0005519 and circHIPK3 in the modulation of T-cell apoptosis, differentiation and secretion of cytokines. This review summarizes the latest news and regulatory roles of these ncRNAs on the function of T cells, with widespread implications on the pathophysiology of autoimmune disorders and cancer.

Keywords: T cell; autoimmune; cancer; circRNA; lncRNA; miRNA.

Figure 1

A schematic representation of the role of various non-coding RNAs in modulating the differentiation of T cells via the PI3K/Akt/mTOR and MAPK/ERK signaling cascades. a) The MAPK/ERK pathway can be triggered via several growth factors including PDGF, EGF, NGF, and insulin. Upon receptor dimerization, activation of its tyrosine kinase module could be triggered, subsequently recruiting Grb2 and SOSto the phosphorylated domain, thus creating the Grb2-SOS complex. Furthermore, the GTP binding protein RAS interacts with the Grb-2-SOS complex that in turn leads to the activation of RAS. Activated GTP-bound RAS plays an effective role in upregulating the phosphorylation of MEK1/2 (MAPKK), which then phosphorylates ERK1/2 (MAPK). Eventually, ERK is transferred to the nucleus where it triggers the activation of various target genes involved in a variety of cellular processes (–29). b) The PI3K/Akt/mTOR signaling is activated by a subset of growth factors such as PI3KCI, which phosphorylates PIP2 to PIP3. PIP3 has an important role in recruiting AKT which gets activated through double phosphorylation (via PDK1 and mTORC2). In addition, activated AKT suppresses TSC2 through phosphorylation. Inactive TSC1/2 complex is able to bind RHEB, which eventually triggers the activation of mTORC1. The mTORC1 has a significant impact on many downstream proteins, such as S6K1/2 and 4EBP1 (30, 31). Besides, exposure to IL-17 results in receptor-mediated activation of Src, MAPKs, and PI3K/Akt signaling cascades (32). Moreover, subsequent to JAK activation, CRKL is phosphorylated by TYK2 that could result in CRKL complexation with STAT5. STATs in turn interacts with individual mediators of the PI3K/AKT signaling cascade (33). Accumulating finding has demonstrated that miR-let-7d-3p via directly suppressing AKT1 could regulate expression level of IL-17 in CD4+ T cells through the AKT1/mTOR signaling pathway (20). In addition, another research has authenticated that overexpression of lncRNA NEAT1 could promote the expression levels of CXCL8 and TNF-α in Sjögren’s syndrome via positively regulating MAPK signaling (34). Green arrows indicate upregulation of target genes modulated via ncRNAs (lncRNAs, and miRNAs), red arrows depict inhibition by these ncRNAs. All the information regarding the role of these ncRNAs in modulating T call differentiation can be seen in and.

Figure 2

A schematic illustration of the role of various noncoding-RNAs in modulating the JAK2/STAT3 and NF-κB signaling pathway as major regulators of T cell function. a) In JAK/STAT pathway, JAKs bind to the receptor, and upon multimerization, upregulation of JAK proteins is mediated via trans-phosphorylation. Consequently, JAKs have a significant part in STATs phosphorylation. After dimerization of STATs, they translocate to the nucleus, where they either activate or suppress several target genes. This cascade is remarkably involved in the control of immune responses. Dysregulation of JAK-STAT signaling is associated with different immune disorders (82, 83). Besides, REG3A, acts as a key molecule for overexpression of the JAK2/STAT3 pathway which effectively contributes to triggering inflammation (84). b) The NF-kB canonical or classical signaling pathway is initiated from the cell surface receptor of pro-inflammatory cytokines and PAMPs containing TNFR, TLR and T/B cell receptor. The activation of IKK complex is triggered via binding of ligand molecules to transfer the signal across the cell surface. This complex generally comprises heterodimer of IKKα and IKKβ catalytic subunits and an IKKγ regulatory subunit. The released NF-kB dimers (most generally the p50–P65 dimer) could be translocated to the nucleus, and bind to DNA to trigger activation of the down-stream gene transcription (–87). In addition, NF-κB signaling cascade could be regulated via TNFAIP3 through deubiquitinating TNFR1-RIP1, IL-1R/TLR4-TRAF6, and NOD2-RIP2 pathways (88). Moreover, canonical NF-kB cascade could be activated by various members of the TNFRSF including GITR, TNFR2, 4-1BB, and DR3 but not OX40 in Treg cells and modulates induction of Foxp3, markers of Th2/Th17 response (89). Mounting studies have revealed that multiple ncRNAs (lncRNAs and miRNAs) have an effective role in as major regulators of T cell function through regulating the JAK/STAT and NF-κB cascades. As an illustration, recent research has detected that downregulation of miR-128-3p could notably reduce the inflammation response of rheumatoid arthritis via attenuating the activity of NF-κB pathway and promote expression of TNFAIP3 (35). Another study has figured out that reducing the expression of lncRNA NEAT1 could lead to suppression of Th17/CD4+ T cell differentiation via downregulating STAT3 expression in rheumatoid arthritis patients (77). Furthermore, upregulation of DQ786243 could play a remarkable role in elevating the expression level of miR-146a through modulating Foxp3, and thereby suppressing the NF-κB signaling cascade in oral lichen planus disease (90). Green arrows indicate upregulation of target genes modulated via ncRNAs (lncRNAs, and miRNAs), red arrows depict inhibition by these ncRNAs. All the information regarding the role of these ncRNAs in modulating T call differentiation can be seen in Tables 1, 2.

Figure 3

A schematic diagram of the role of some ncRNAs in modulating the IL-4-STAT6-GATA3 axis in Th2-cell differentiation. Th2 cell differentiation requires considerable metabolic reprogramming. Upon encountering cognate antigen in the lymph node, naive CD4 T helper cells are differentiated into Th2 cells under the effect of the IL-4-STAT6-GATA3 axis. GATA3 could, in turn, alter the IL4– IL13–IL5 locus to generate a conformation that is reachable by different other transcription factors that are involved in triggering the differentiation of T cells into T H2 cells (117). Growing evidence has confirmed that the interactions between CircHIPK3, LncGAS5, and miR-495 could play a crucial role in the modulation of Th2 differentiation in allergic rhinitis (116). Green arrows indicate upregulation of target genes by ncRNAs (lncRNA, and circRNA), red arrows depict inhibitory effects of by these ncRNAs.