The role of miRNAs in T helper cell development, activation, fate decisions and tumor immunity

Abstract

T helper (Th) cells are central members of adaptive immunity and comprise the last line of defense against pathogen infection and malignant cell invasion by secreting specific cytokines. These cytokines then attract or induce the activation and differentiation of other immune cells, including antibody-producing B cells and cytotoxic CD8⁺ T cells. Therefore, the bidirectional communication between Th cells and tumor cells and their positioning within the tumor microenvironment (TME), especially the tumor immune microenvironment (TIME), sculpt the tumor immune landscape, which affects disease initiation and progression. The type, number, and condition of Th cells in the TME and TIME strongly affect tumor immunity, which is precisely regulated by key effectors, such as granzymes, perforins, cytokines, and chemokines. Moreover, microRNAs (miRNAs) have emerged as important regulators of Th cells. In this review, we discuss the role of miRNAs in regulating Th cell mediated adaptive immunity, focusing on the development, activation, fate decisions, and tumor immunity.

Keywords: activation; development; fate decisions; miRNAs; T helper cell; tumor immunity; tumor microenvironment.

Figure 1

miRNAs in Th cell development. HSC, hematopoietic stem cells; LT-HSC, long-term HSC; ST-HSC, short-term HSC; MPP, multipotent progenitor; CMP, common myeloid progenitor; CLP, common lymphoid progenitor; ETP, early T cell progenitor; DN, double-negative; DP, double-positive.

Figure 2

miRNAs in Th1 cell differentiation and fate decision. IL-12, interleukin-12; IFN-γ, interferon-gamma; STAT1 or STAT4, signal transducer and activator of transcription 1 or 4; T-bet, T-Box expressed in T cells; IL-12R2β, interleukin-12 receptor 2 beta.

Figure 3

miRNAs in Th2 cell differentiation and fate decision. IL-4 or IL-2, interleukin-4 or 2; STAT5 or STAT6, signal transducer and activator of transcription 5 or 6; GATA-3, GATA binding protein 3; JunB, JunB proto-oncogene, AP-1 transcription factor subunit; c-Maf, proto-oncogene c-Maf; AP1, Jun proto-oncogene; NFAT, nuclear factor of activated T-cells; NF-κB, nuclear factor kappa B subunit 1.

Figure 4

miRNAs in Th17 cell differentiation and fate decision. IL-23 or IL-6 or IL-2, interleukin- 23 or 6 or 2; TGF-β, transforming growth factor beta 1; STAT3 or STAT5, signal transducer and activator of transcription 3 or 5; RORγt, retinoid-related orphan receptor-gamma; SMAD2 or SMAD3 or SMAD4, SMAD Family Member 2 or 3 or 4; HIF-1α, hypoxia inducible factor 1 subunit alpha; OGT, O-linked N-Acetylglucosamine (GlcNAc) transferase; NFATC2, nuclear factor of activated T-cells 2; TRAF6, TNF receptor associated factor 6; AP1, Jun proto-oncogene; NFAT, nuclear factor of activated T-cells; NF-κB, nuclear factor kappa B subunit 1.

Figure 5

miRNAs in Tfh cell differentiation and fate decision. IL-21 or IL-6 or IL-2, interleukin-21 or 6 or 2; ICOS, inducible T cell co-stimulator; STAT3 or STAT5, signal transducer and activator of transcription 3 or 5; BCL-6, B-cell lymphoma 6 protein; BLIMP1, B-lymphocyte-induced maturation protein 1; FOSL2, FOS like 2, AP-1 transcription factor subunit; PELI1, pellino E3 ubiquitin protein ligase 1; IRAK1, interleukin 1 receptor associated kinase 1; AP1, Jun proto-oncogene; NFAT, nuclear factor of activated T-cells; NF-κB, nuclear factor kappa B subunit 1.

Figure 6

miRNAs in Treg cell differentiation and fate decision. IL-6 or IL-2, interleukin-6 or 2; TGF-β, transforming growth factor beta 1; STAT3 or STAT5, signal transducer and activator of transcription 3 or 5; FOXP3, Forkhead box P3; SMAD2 or SMAD3, SMAD Family Member 2 or 3; HIF-1α, hypoxia inducible factor 1 subunit alpha; AP1, Jun proto-oncogene; NFAT, nuclear factor of activated T-cells; FOXO1, Forkhead box O1; CTLA4, cytotoxic T-lymphocyte associated protein 4.