MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression

Abstract

Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a “cytokine storm” with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm’s initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host’s ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa-associated invariant T (MAIT) cells, as the most powerful source of pro-inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA-DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD-scid IL-2Rγnull mice to demonstrate for the first time that: i) mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB); ii) the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT) or γδ T cells, and is characterized by production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-2, but not IL-17A; iii) high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1) participation, is required for MAIT cell activation; iv) MAIT cell responses to SEB can occur in a T cell receptor (TCR) Vβ–specific manner but are largely contributed by IL-12 and IL-18; v) as MAIT cells are primed by SAgs, they also begin to develop a molecular signature consistent with exhaustion and failure to participate in antimicrobial defense. Accordingly, they upregulate lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-3 (TIM-3), and/or programmed cell death-1 (PD-1), and acquire an anergic phenotype that interferes with their cognate function against Klebsiella pneumoniae and Escherichia coli; vi) MAIT cell hyperactivation and anergy co-utilize a signaling pathway that is governed by p38 and MEK1/2. Collectively, our findings demonstrate a pathogenic, rather than protective, role for MAIT cells during infection. Furthermore, we propose a novel mechanism of SAg-associated immunosuppression in humans. MAIT cells may therefore provide an attractive therapeutic target for the management of both early and late phases of severe SAg-mediated illnesses.

MAIT cell-mediated cytotoxicity: Roles in host defense and therapeutic potentials in infectious diseases and cancer

“…Mucosa‐associated invariant T (MAIT) cells have come under increasing scrutiny in recent years. They may fulfill protective or pathogenic functions in infectious diseases and malignancies . MAIT cells are best known for their immunomodulatory cytokine production capacity.…”

“…MAIT cells constitutively express several cytokine receptor components such as CD127 (IL‐7Rα), CD212 (IL‐12Rβ1), CD218a (IL‐18Rα), and CD218b (IL‐18Rβ) . Therefore, acting alone or in additive/synergistic combinations, IL‐2, IL‐7, IL‐12, IL‐15, IL‐18, IFN‐α, and IFN‐β can promote robust inflammatory and/or cytotoxic responses by MAIT cells .…”

MAIT cells and microbial immunity

“…The differentiation required MAIT cell-dependent production of GM-CSF, and the role of IL-12 or IL-18 in MAIT cell activation was not investigated. Shaler et al have demonstrated another MR1-independent pathway for MAIT cell activation through bacterial superantigens 24 . Overall, given the localization of MAIT cells at common sites of infection, both MR1-independent and MR1-dependent MAIT cell activity is likely to play a role in defense against certain infections in vivo .…”

“…It has been widely observed that they produce the pro-inflammatory cytokines IFN-γ and TNF-α 4–8,10,24,38,62,63 . MAIT cell effector function in response to TCR signaling is triggered more rapidly than conventional T cells.…”

645. Mucosal-Associated Invariant T cells in Renal Tissue From Patients With Recurrent Urinary Tract Infections

“…Mucosal‐associated invariant T (MAIT) cells are innate‐like T cells that play a role in the antibacterial and antifungal response by recognizing riboflavin metabolites produced by these organisms 9 . MAIT cells comprise 0.1% to 10% of the circulating T‐cell population, 10 are abundant in the liver, lungs, intestine, stomach, kidney, and the female genital mucosa 11–15 and can respond rapidly, that is, within hours, to a wide range of bacteria 16,17 . MAIT cells are characterized by the expression of the semi‐invariant Vα7.2‐Jα12/20/33 chain as a part of their T‐cell receptor (TCR).…”