A divergent transcriptional landscape underpins the development and functional branching of MAIT cells

Abstract

MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing–based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 “mature” MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ–producing MAIT1 cells and interleukin-17–producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)–deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans.

Tc17 biology and function: Novel concepts

“…MAIT cells develop intrathymically through a three-stage process in mice and humans. At stage 3, which resembles mature MAIT cells in peripheral organs, the intrathymical MAIT cells comprise two functionally different subpopulations: MAIT1 cells, positive for T-bet and IFN-γ, and MAIT17 cells characterized by RORγt and IL-17 expression [49,50]. Similar to Tc17 cells, MAIT1 and MAIT17 cells contribute to protection against pathogens by secretion of cytokines including IL-17 and IFN-γ in mice and humans.…”

“…for MAIT1 [50,51] In humans: CD3 + TCRα7. [54,55] Localization at steady state Very rare in SPF-bred WT mice [10,36] Lamina propria [57] Lamina propria, barrier tissues, peripheral blood, liver [51] Thymus, secondary lymphoid organs, barrier tissues [54] Reported protective functions Skin homeostasis detected CD3 +…”

Functional MAIT Cells Are Associated With Reduced Simian–Human Immunodeficiency Virus Infection

“…Naïve RM tended to have lower MAIT cells in blood (∼0.53%), spleen (∼0.90%), and lung (∼1.09%) compared to the rectum (∼2.3%, mean) and liver (∼9.8%, mean) ( Figure 1D). A key feature of the MAIT cell developmental pathway is the expression of PLZF, and cells have been shown to express the transcription factor PLZF in humans and mice (3,6,28,29); thus, we further characterized the macaque CD8 + CD161 ++ TCR7.2 + cells for the expression of PLZF. We observed that the majority of macaque blood CD161 ++ TCR7.2 + CD8 + cells express PLZF ( Figure 1E).…”

Human MAIT cell cytolytic effector proteins synergize to overcome carbapenem resistance inEscherichia coli

“…Interestingly, cytolytic proteins are differentially expressed during the development of human MAIT cells, with the mature subsets expressing more of these effector proteins [44]. In adult human female genital tract, oral mucosa, and placental tissues, MAIT cells express low level of GrzB at steady state [12,[45][46][47], suggesting that the regulation of cytolytic effector proteins in tissues may differ from that of blood MAIT cells.…”