MicroRNA-155 Regulates MAIT1 and MAIT17 Cell Differentiation

Abstract

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that develop in the thymus through three maturation stages to acquire effector function and differentiate into MAIT1 (T-bet+) and MAIT17 (RORγt+) subsets. Upon activation, MAIT cells release IFN-γ and IL-17, which modulate a broad spectrum of diseases. Recent studies indicate defective MAIT cell development in microRNA deficient mice, however, few individual miRNAs have been identified to regulate MAIT cells. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affect some immune cell development, but its role in MAIT cell development remains unclear. To address whether miR-155 is required for MAIT cell development, we performed gain-of-function and loss-of-function studies. We first generated a CD4Cre.miR-155 knock-in mouse model, in which miR-155 is over-expressed in the T cell lineage. We found that overexpression of miR-155 significantly reduced numbers and frequencies of MAIT cells in all immune organs and lungs and blocked thymic MAIT cell maturation through downregulating PLZF expression. Strikingly, upregulated miR-155 promoted MAIT1 differentiation and blocked MAIT17 differentiation, and timely inducible expression of miR-155 functionally inhibited peripheral MAIT cells secreting IL-17. miR-155 overexpression also increased CD4–CD8+ subset and decreased CD4–CD8– subset of MAIT cells. We further analyzed MAIT cells in conventional miR-155 knockout mice and found that lack of miR-155 also promoted MAIT1 differentiation and blocked MAIT17 differentiation but without alteration of their overall frequency, maturation and function. Overall, our results indicate that adequate miR-155 expression is required for normal MAIT1 and MAIT17 cell development and function.

Emerging Roles of Mucosal-Associated Invariant T Cells in Rheumatology

“…MiRNAs may participate in the transition from stage 1 to 2, because in the absence of miR-181a/b-1, thymic MAIT cells show low expressions of ROR gt and T -bet (23). The maturation from stage 2 to stage 3 and acquisition of effector function are PLZF dependent, and commensal bacteria along with IL-18 play an important role in the process (17) MAIT17 cells differentiation (25)(26)(27). Recently, MAIT2 cells that express PLZF have been defined using single-cell RNA sequencing analysis, which are considered as developmental intermediates of MAIT1 and MAIT17 cells (28).…”

“…At stage 3, MAIT cells expressing CD161 + CD27 pos-low (CD24 - CD44 + in mice) exhibit interferon (IFN)-γ-producing T-bet + (MAIT-1) sublineage or IL-17 A producing RORγt + (MAIT-17) ( 24 ). IL-2/IL-15 receptor β chain, inducible costimulatory (ICOS), the transcription factor (TF) Bcl11b and miR-155 are involved in regulating MAIT1 and MAIT17 cells differentiation ( 25 – 27 ). Recently, MAIT2 cells that express PLZF have been defined using single-cell RNA sequencing analysis, which are considered as developmental intermediates of MAIT1 and MAIT17 cells ( 28 ).…”

Seq2MAIT: A Novel Deep Learning Framework for Identifying Mucosal Associated Invariant T (MAIT) Cells

“…This becomes apparent when identifying the subset of MAIT cells, e.g. MAIT 1 vs MAIT 17 58,64 , is critical for understanding the biological process under investigation. Hence, Seq2MAIT is not intended as a replacement for flow-cytometry-based methods but as a complementary method that can be used to identify MAIT cells in samples where living cells are not available or to prioritize samples for further characterization using flow-cytometry or scRNA-Seq based methods.…”

Regulation and Functions of Protumoral Unconventional T Cells in Solid Tumors

“…Intervention in TME metabolism may include supplementation of cancer patients with glucose, nucleic acids and/or amino acids to enhance or rewire UT cell cytotoxic functions, as recently shown for other cytotoxic lymphocytes [ 208 , 209 , 210 , 211 , 212 ]. In addition, UT cell effector functions are also controlled by post-transcriptional regulators such as epigenetic mechanisms [ 213 ] and miRNA [ 214 , 215 , 216 ]. Thus, the use of epigenetic modifiers and miRNA inhibitors is worth investigating.…”