MAIT Cells Are Major Contributors to the Cytokine Response in Group A Streptococcal Toxic Shock Syndrome

Abstract

Streptococcal toxic shock syndrome (STSS) is a rapidly progressing, life-threatening, systemic reaction to invasive infection caused by group A streptococci (GAS). GAS superantigens are key mediators of STSS through their potent activation of T cells leading to a cytokine storm and consequently vascular leakage, shock, and multiorgan failure. Mucosal-associated invariant T (MAIT) cells recognize MR1-presented antigens derived from microbial riboflavin biosynthesis and mount protective innate-like immune responses against the microbes producing such metabolites. GAS lack de novo riboflavin synthesis, and the role of MAIT cells in STSS has therefore so far been overlooked. Here we have conducted a comprehensive analysis of human MAIT cell responses to GAS, aiming to understand the contribution of MAIT cells to the pathogenesis of STSS. We show that MAIT cells are strongly activated and represent the major T cell source of IFNγ and TNF in the early stages of response to GAS. MAIT cell activation is biphasic with a rapid TCR Vβ2-specific, TNF-dominated response to superantigens and a later IL-12- and IL-18-dependent, IFNγ-dominated response to both bacterial cells and secreted factors. Depletion of MAIT cells from PBMC resulted in decreased total production of IFNγ, IL-1β, IL-2, and TNFβ. Peripheral blood MAIT cells in patients with STSS expressed elevated levels of the activation markers CD69, CD25, CD38, and HLA-DR during the acute compared with the convalescent phase. Our data demonstrate that MAIT cells are major contributors to the early cytokine response to GAS, and are therefore likely to contribute to the pathological cytokine storm underlying STSS.

T Cell Immunity to Bacterial Pathogens: Mechanisms of Immune Control and Bacterial Evasion

“…Such an effect was dependent on SAg pre-exposure, as a contrasting phenotype was seen when SEB was administered following a pre-existing influenza infection, highlighting the potential core differences in how SAgs can function when exposed to naïve or memory virus-specific CD8 + T cells. SAgs possess the ability to bind αβ TCRs on MHC-restricted CD4 + or CD8 + T cells, but also target unconventional, antimicrobial T cell populations bearing αβ TCRs, such as MAIT cells [ 273 , 274 ] and iNKT cells [ 275 , 276 ] ( Figure 3 ). However, SAgs can also recognise γδ T cells, demonstrating that these toxins can bind TCRs lacking TCR α- or β-chains, and such interaction by certain SAgs involves TRGV9 + γδ TCRs [ 277 , 278 , 279 , 280 ].…”

“…However, SAgs can also recognise γδ T cells, demonstrating that these toxins can bind TCRs lacking TCR α- or β-chains, and such interaction by certain SAgs involves TRGV9 + γδ TCRs [ 277 , 278 , 279 , 280 ]. MAIT cells typically encode TCRs with biased TRBV20-1 and TRBV6-2/6-3 gene usage [ 192 ], exposing them to SAgs such as SEB, TSST-1, and SpeC, which was proven in recent studies [ 273 , 274 ]. Indeed, SAg-triggered MAIT cells produce substantially high levels of effector cytokines (e.g., IFNγ), through an IL-12/IL-18-dependent mechanism that does not involve MR1.…”

“…Indeed, SAg-triggered MAIT cells produce substantially high levels of effector cytokines (e.g., IFNγ), through an IL-12/IL-18-dependent mechanism that does not involve MR1. Such hyperactivation induces MAIT cell anergy both in vitro and in vivo, in humanized mouse models, impeding their anti-bacterial capabilities [ 273 , 274 ]. Highly activated MAIT cells form major contributors of cytokines, produced in the acute phase of streptococcal TSS (STSS), despite the GAS species lacking de novo riboflavin synthesis, indicating that SAg-driven MAIT cell activation underlies the cytokine storm seen in STSS patients [ 274 ].…”

“…Such hyperactivation induces MAIT cell anergy both in vitro and in vivo, in humanized mouse models, impeding their anti-bacterial capabilities [ 273 , 274 ]. Highly activated MAIT cells form major contributors of cytokines, produced in the acute phase of streptococcal TSS (STSS), despite the GAS species lacking de novo riboflavin synthesis, indicating that SAg-driven MAIT cell activation underlies the cytokine storm seen in STSS patients [ 274 ]. All of this demonstrates the considerable impact SAgs have in clinical settings and the direct effects they have on both conventional αβ T cells and unconventional αβ or γδ T cells.…”

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

“…In the absence of TCR-dependent antigen recognition, MAIT cells can be activated by cytokines, including IL-12 and IL-18 ( 54 , 106 – 108 ), and by super-antigens ( 109 ). In one study, the MAIT cell response in group A streptococcus (GAS) infection appeared to contain both TCRβ-dependent (super-antigen) and independent activation ( 110 ). Cytokines likely drive the MAIT cell activation observed in viral infections and contribute to their response during bacterial infection ( 111 ).…”