MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets

Abstract

Mucosal-associated invariant T (MAIT) cells are an innate-like T-cell population restricted by the non-polymorphic, major histocompatibility complex class I-related protein 1, MR1. MAIT cells are activated by a broad range of bacteria through detection of riboflavin metabolites bound by MR1, but their direct cytolytic capacity upon recognition of cognate target cells remains unclear. We show that resting human MAIT cells are uniquely characterized by a lack of granzyme (Gr) B and low perforin expression, key granule proteins required for efficient cytotoxic activity, but high levels of expression of GrA and GrK. Bacterial activation of MAIT cells rapidly induced GrB and perforin, licensing these cells to kill their cognate target cells. Using a novel flow cytometry-based killing assay, we show that licensed MAIT cells, but not ex vivo MAIT cells from the same donors, can efficiently kill Escherichia coli-exposed B-cell lines in an MR1- and degranulation-dependent manner. Finally, we show that MAIT cells are highly proliferative in response to antigenic and cytokine stimulation, maintaining high expression of GrB, perforin, and GrA, but reduced expression of GrK following antigenic proliferation. The tightly regulated cytolytic capacity of MAIT cells may have an important role in the control of intracellular bacterial infections, such as Mycobacterium tuberculosis.

Maximal exercise increases mucosal associated invariant T cell frequency and number in healthy young men

“…As 10% of CD8 + T cell express MAIT cell markers (Cosgrove et al 2013;Dusseaux et al 2011;Fergusson et al 2016;Walker et al 2012), similar to observations from the current study, this indicates that CD8 + Vα7.2 + CD161 + MAIT cells are a substantial population with particular relevance given the preferential mobilization of CD8 + cells following exercise (Campbell et al 2008;Gannon et al 2001;Simpson et al 2008). While CTLs and MAIT cells share similar cytotoxicity mechanisms (Kurioka et al 2015), the traditional targets of these respective cells are viral and bacterial infections (Dusseaux et al 2011;Gold et al 2010), although recent evidence argues otherwise . However, failing to exclude MAIT cells when assessing classic CTL function likely underestimates normalized cytotoxic function.…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…Additionally, CD56 bright NK cells are known for their proliferative capacity in response to cytokines;88 for example, liver‐resident CD49a+ NK cells have been found to express high levels of CD25, and were able to proliferate in response to low doses of IL‐2 89. CD161++ CD8+ T‐cells are also highly proliferative upon stimulation with IL‐12 and IL‐15 compared with the CD161+ CD8+ T‐cell counterparts 90, 91…”

“…Resting CD161++ CD8+ T‐cells, in particular the MAIT cells, express no GrB and little perforin, and instead are uniquely enriched for GrK expression 90. In turn, CD161+ CD8+ T‐cells are enriched for GrB and perforin expression, even compared with their CD161− CD8+ T‐cell counterparts 16.…”

“…1). 48, 100 However, both CD56 bright NK cells51 and CD161++ CD8+ T‐cells (including the MAIT cells)90 can upregulate GrB and perforin, and become efficient killer cells, after activation. For example, the CD56 bright NK cell population can kill activated autologous CD4+ T‐cells in MS 101, 102.…”

Lights on MAIT cells, a new immune player in liver diseases

“…Bacteria lacking the vitamin B2 (riboflavin) synthesis pathway are unable to activate MAIT cells through their specific TCR [9][10][11][12]. IL-12 and IL-18 cytokines can also activate MAIT cells in a TCR-independent manner since these innate-like T cells express high level of 7,13,14]. Recent studies have reported a critical role of MAIT cells in mucosal immune defense during bacterial infections [15].…”