Interleukin-18 Is Critical for Mucosa-Associated Invariant T Cell Gamma Interferon Responses to Francisella SpeciesIn Vitrobut NotIn Vivo

Abstract

Mucosa-associated invariant T (MAIT) cells are a subset of innate T cells that express a semi-invariant Vα chain paired with limited Vβ chains. MAIT cells are activated by riboflavin metabolite derivatives presented by the nonpolymorphic major histocompatibility complex class I (MHC-I)-like molecule MR1. The precise mechanisms required to activate MAIT cells are an area of intense interest. Here we used two closely related intracellular pathogens with distinct inflammasome activation phenotypes to probe the role of innate cytokines in MAIT cell activation. Using an assay containing transgenic murine MAIT cells, we show that macrophages infected with, a strong inflammasome activator, released high levels of interleukin-18 (IL-18) and stimulated high levels of MAIT cell gamma interferon (IFN-γ) through a partially MR1-independent pathway. In contrast, macrophages infected with live vaccine strain (LVS), a weak inflammasome activator, generated little IL-18 and stimulated low MAIT cell IFN-γ through an MR1-dependent pathway. By manipulating the quantities of IL-18 in these cultures, we show that the IL-18 concentration is sufficient to influence the magnitude of MAIT cell IFN-γ production. Correspondingly, infected IL-18-deficient macrophages failed to induce substantial MAIT cell IFN-γ. In contrast, we found that MAIT cell IFN-γ production in the lungs of IL-18-deficient mice was not significantly different from that in WT mice during LVS pulmonary infection. Overall, we demonstrate that while IL-18 is essential for the MAIT cell IFN-γ response , it is not essential for MAIT cell IFN-γ production during LVS pulmonary infection, suggesting that additional signals can drive MAIT cell IFN-γ production .

Mucosal-associated invariant T cells and disease

“…Furthermore, peripheral blood mononuclear cells or the THP1 monocytic cell line exposed to E. coli (riboflavin-synthesizing) or E. faecalis (non-riboflavin-synthesizing) produce IL-12 and IL-18 via a Toll-like receptor 8 (TLR8) pathway, and both cytokines are required for MAIT cell activation 59 . However, a recent study showed that although IL-18 is required for MAIT cell activation by F. tularensis in vitro, this cytokine is not essential for MAIT cell IFNγ production in in vivo infection 49 . Bacterial infection in vivo might induce MAIT cell activation through a more complex immune cell crosstalk, involving TLRs expressed by antigen-presenting cells (APCs) 48,59 .…”

“…1). MAIT cells express high levels of IL-18 receptor (IL-18R) and IL-12R, and IL-18 and IL-12 have emerged as the major cytokines that activate MAIT cells upon bacterial or viral infection 43,45,[49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] ( TaBle 2). During bacterial infection, blockade or deletion of the IL-12p40 subunit impairs MAIT cell control of intracellular growth of F. tularensis and M. bovis 43,45 .…”

“…The effect of IL-18 on MAIT cells in bacterial infection is more uncertain. In vitro studies have shown that F. tularensis and Enterococcus faecalis, whether or not they produce riboflavin, are able to stimulate the production of IFNγ by MAIT cells in an IL-12-and/or IL-18dependent manner 49,50 . Furthermore, peripheral blood mononuclear cells or the THP1 monocytic cell line exposed to E. coli (riboflavin-synthesizing) or E. faecalis (non-riboflavin-synthesizing) produce IL-12 and IL-18 via a Toll-like receptor 8 (TLR8) pathway, and both cytokines are required for MAIT cell activation 59 .…”

Antigen Recognition by MR1-Reactive T Cells; MAIT Cells, Metabolites, and Remaining Mysteries

“…MAIT cells have been analyzed in several mouse models of bacterial infection, demonstrating their role in protecting against pathogenic organisms such as Francisella tularensis ( 33 , 70 ), Klebsiella pneumoniae ( 32 ), Mycobacterium bovis BCG ( 54 ), and Legionella longbeachae ( 34 ). Riboflavin-based antigens are likely produced not only by pathogenic microorganisms during infection, but also by commensal microorganisms.…”

“…MAIT cells have been described as “innate-like” rapid responders, with a memory-like phenotype. However, like conventional T cells, MR1-antigen alone is insufficient to drive an optimal MAIT cell response, with co-stimuli including cytokines and/or surface co-receptors required ( 67 ) and able to enhance MAIT responses to antigen stimulation ( 96 – 99 ), although in vitro findings have not always translated to in vivo studies ( 70 ). Additionally, polarizing effects on MAIT cell function have been demonstrated.…”