Activation and In Vivo Evolution of the MAIT Cell Transcriptome in Mice and Humans Reveals Tissue Repair Functionality

Abstract

Highlights d We define the basic transcriptome of an activated MAIT cell in mice and humans d During acute infection, the MAIT cell transcriptome is most similar to iNKT cells d After the resolution of infection, MAIT cells more closely resemble gd T cells d Both human-and murine-activated MAIT cells express a strong tissue repair signature

TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions

“…We performed a data integration analysis by fusing RNA-seq datasets containing mouse data from activation studies in vivo and in vitro (Hinks et al, 2019) with our human data and applying a protocol for such integration . First, we examined how our data aligned with those obtained by Hinks et al (2019), who examined mouse MAIT cell activation in vitro (5-OP-RU stimulation) and in vivo (bacterial challenge), because these were shown to align with activated H2M3-restricted cells from publicly available data from Linehan et al (2018) (Figure 6). The accompanying dendrogram shows the close transcriptional relationship between our in vitro-activated human T cells and those in the mouse.…”

Study of MAIT Cell Activation in Viral Infections In Vivo

“…MAIT cells are rare in specific pathogen-free mice [6], typically comprising about 1 Â 10 4 recoverable pulmonary MAIT cells in an infection-naïve adult C57BL/6 mouse. Therefore, for adoptive transfer experiments, the MAIT cell population should first be expanded using intranasal infection [15] or immunization (5-OP-RU with TLR agonists) [3,15] (see Note 5). When planning the adoptive transfer experiment, estimate that one S. Typhimurium BRD509-infected mouse will yield 1-2 Â 10 6 sorted MAIT cells, which are enough for 10-20 recipient mice (10 5 MAIT cells/RAG2 À/À γC À/À mouse in this case).…”

“…MAIT cells are relatively recently described innate-like lymphocytes, with similarities to the invariant natural killer T (iNKT) and γδ T cell subsets [1][2][3][4]. They are the most abundant innate-like population in the lungs in humans [5] though relatively rare in specific pathogen-free mice [6] and show a striking evolutionary conservation between diverse species of mammals [7].…”

“…These molecular intermediates exist only in microbes but not in mammals, and therefore constitute a signature of microbial infection. This property implicates MAIT cells in anti-bacterial host defense, and potentially also in other roles such as tissue repair [3]. However, in addition to their TCR-dependent functions, they can be activated in a TCR-independent manner via cytokines including IL-12, -15, -18, and type I interferon [10][11][12].…”

“…Pulmonary MAIT cells can be expanded using any source of 5-OP-RU and an appropriate TLR agonist [15,17]. A systematic assessment of effective TLR agonists has shown strong MAIT cell expansion 7 days after intranasal inoculation with 76 pmol 5-OP-RU on days 1, 2, and 4 in combination with a single dose of agonist on day 1 to TLR3 (high molecular weight poly I:C), TLR4 (lipopolysaccharide from E. coli), TLR2/6 (FSL-1 (Pam2CGDPKHPKSF)), or TLR9 (CpG ODN1826), but not with agonists of TLR1/2 (Pam3CSK4), TLR2, TLR5, TLR7 [3]. Each inoculum should be instilled in 50 μL PBS.…”