Signals that control MAIT cell function in healthy and inflamed human tissues

Abstract

SummaryMucosal‐associated invariant T (MAIT) cells have a semi‐invariant T‐cell receptor that allows recognition of antigen in the context of the MHC class I‐related (MR1) protein. Metabolic intermediates of the riboflavin synthesis pathway have been identified as MR1‐restricted antigens with agonist properties. As riboflavin synthesis occurs in many bacterial species, but not human cells, it has been proposed that the main purpose of MAIT cells is antibacterial surveillance and protection. The majority of human MAIT cells secrete interferon‐gamma (IFNg) upon activation, while some MAIT cells in tissues can also express IL‐17. Given that MAIT cells are present in human barrier tissues colonized by a microbiome, MAIT cells must somehow be able to distinguish colonization from infection to ensure effector functions are only elicited when necessary. Importantly, MAIT cells have additional functional properties, including the potential to contribute to restoring tissue homeostasis by expression of CTLA‐4 and secretion of the cytokine IL‐22. A recent study provided compelling data indicating that the range of human MAIT cell functional properties is explained by plasticity rather than distinct lineages. This further underscores the necessity to better understand how different signals regulate MAIT cell function. In this review, we highlight what is known in regards to activating and inhibitory signals for MAIT cells with a specific focus on signals relevant to healthy and inflamed tissues. We consider the quantity, quality, and the temporal order of these signals on MAIT cell function and discuss the current limitations of computational tools to extrapolate which signals are received by MAIT cells in human tissues. Using lessons learned from conventional CD8 T cells, we also discuss how TCR signals may integrate with cytokine signals in MAIT cells to elicit distinct functional states.

A Comprehensive Investigation of Stimulatory Agents on MAIT and Vα7.2+/CD161− T Cell Response and Effects of Immunomodulatory Drugs

“…Recently, Konecny et al summarized MAIT cell signals that integrate different functions in healthy and inflamed tissues. They also highlighted the complexity of the computational exploration of cell–cell communication using single-cell data [ 28 ]. Fergusson et al reported that MAIT cells are characterized by high expression levels of multi-drug resistance protein 1 (MDR1), an ATP-binding cassette-multi-drug efflux protein.…”

Insights into the tissue repair features of MAIT cells

“…Recent evidence shows that MAIT cells play a significant role in the immune response to SARS-CoV-2. In COVID-19 patients, circulating MAIT cells significantly decrease and become enriched in the airways ( 109 – 114 ). The remaining blood MAIT cells are activated, with increased CD69, CD38, HLA-DR, CD56, and granzyme B expression, along with decreased CXCR3 expression.…”

“…The remaining blood MAIT cells are activated, with increased CD69, CD38, HLA-DR, CD56, and granzyme B expression, along with decreased CXCR3 expression. Airway MAIT produce IL-17A and TNF, associated with chemokines like CXCL10 and CX3CL1 ( 109 , 112 ). Regarding clinical outcomes, current research shows inconsistent results.…”

“…For instance, fully utilizing current organoid culture techniques may be beneficial. Organoids, self-organizing, miniaturized organs derived from a series of stem cells, replicating key structural and functional features of their in vivo counterparts ( 109 , 120 – 124 ). Constructing 3D models of human ex vivo skin, gastrointestinal tract, and other organoids, and exploring the interaction between co-culture systems and immune cells, can provide deeper insights into the functional aspects of MAIT cells in organoid models under different disease conditions.…”

“…Constructing 3D models of human ex vivo skin, gastrointestinal tract, and other organoids, and exploring the interaction between co-culture systems and immune cells, can provide deeper insights into the functional aspects of MAIT cells in organoid models under different disease conditions. This includes migration, cytokine production, tissue repair, and antimicrobial activity ( 109 ). Additionally, these models can help describe the crosstalk between MAIT cells and resident mucosal immune cells and the consequent impacts on mucosal integrity and immunity.…”