Rapid and Rigorous IL-17A Production by a Distinct Subpopulation of Effector Memory T Lymphocytes Constitutes a Novel Mechanism of Toxic Shock Syndrome Immunopathology

Szabo, Peter A.; Goswami, Ankur; Mazzuca, Delfina M.; Kim, Kyoungok; O’Gorman, David B.; Hess, David A.; Welch, Ian; Young, Howard A.; Singh, Bhagirath; McCormick, John K.; Haeryfar, S. M. Mansour

doi:10.4049/jimmunol.1601366

Cited by 35 publications

(38 citation statements)

References 94 publications

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“…The difference in terms of time of administration is justified by earlier observations that found a significant increase of Th17 cytokines following 7 days from Aβ injection (Zhang et al, ; Zhang et al, ). Moreover, very robust effects were observed when the Ab was administered at dose of 1 μg·μl −1 , compared with the isotype Control or Ab itself, consistent with previous in vivo reports (Fischer et al, ; Mi et al, ; Szabo et al, ). It is known that a major, yet unmet, objective of neuroprotective or anti‐neurodegenerative treatments is to arrest or to slow down the rapid progression of cognitive impairment.…”

Section: Discussionsupporting

confidence: 89%

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

Cristiano

Volpicelli

Lippiello

et al. 2019

British J Pharmacology

106

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Background and purpose Alzheimer's disease (AD) is a common neurodegenerative disease characterized by a neuroinflammatory state, and to date, there is no cure and its treatment represents a large unmet clinical need. The involvement of Th17 cells in the pathogenesis of AD‐related neuroinflammation has been reported in several studies. However, the role of the cytokine, IL‐17 has not been well addressed. Herein, we investigate the effects of IL‐17 neutralizing antibody (IL‐17Ab) injected by i.c.v. or intranasal (IN) routes on amyloid‐β (Aβ)‐induced neuroinflammation and memory impairment in mice. Experimental approach Aβ1–42 was injected into cerebral ventricles of adult CD1 mice. These mice received IL‐17Ab via i.c.v. either at 1 h prior to Aβ1–42 injection or IN 5 and 12 days after Aβ1–42 injection. After 7 and 14 days of Aβ1–42 administration, we evaluated olfactory, spatial and working memory and performed biochemical analyses on whole brain and specific brain areas. Key results Pretreatment with IL‐17Ab, given, i.c.v., markedly reduced Aβ1–42‐induced neurodegeneration, improved memory function, and prevented the increase of pro‐inflammatory mediators in a dose‐dependent manner at 7 and 14 days. Similarly, the double IN administration of IL‐17Ab after Aβ1–42 injection reduced neurodegeneration, memory decline, and the levels of proinflammatory mediators and cytokines. Conclusion and implications These findings suggest that the IL‐17Ab reduced neuroinflammation and behavioural symptoms induced by Aβ. The efficacy of IL‐17Ab IN administration in reducing Aβ1–42 neurodegeneration points to a possible future therapeutic approach in patients with AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Section: Discussionsupporting

confidence: 89%

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

Cristiano

Volpicelli

Lippiello

et al. 2019

British J Pharmacology

106

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“…Furthermore, i NKT cells are indispensable for SEB-induced early IL-17 production [50]. Whether these findings are coincidental or mechanistically linked remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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“…SAg-mediated T cell activation results in production of several cytokines, but IL-17A and IFNγ appear to be primary drivers of the early response to these toxins. In particular, the secretion of IL-17A has been traced to a subset of CD4 + effector memory T cells in the early stages of activation [ 102 , 103 ]. Blockade of IL-17A protects HLA-DR4 transgenic mice from SEB-induced TSS, preventing the secretion of downstream cytokines in the cascade including IL-6 and TNFα [ 103 ].…”

Section: Superantigens In S Aureus Pathogenesimentioning

confidence: 99%

“…In particular, the secretion of IL-17A has been traced to a subset of CD4 + effector memory T cells in the early stages of activation [ 102 , 103 ]. Blockade of IL-17A protects HLA-DR4 transgenic mice from SEB-induced TSS, preventing the secretion of downstream cytokines in the cascade including IL-6 and TNFα [ 103 ]. Thus, IL-17A overproduction appears to contribute to the pathology of TSS to drive the immune response in favour of a Th17 response, and away from a Th1 response, at least in the early stages of activation [ 103 ].…”

Section: Superantigens In S Aureus Pathogenesimentioning

confidence: 99%

“…Blockade of IL-17A protects HLA-DR4 transgenic mice from SEB-induced TSS, preventing the secretion of downstream cytokines in the cascade including IL-6 and TNFα [ 103 ]. Thus, IL-17A overproduction appears to contribute to the pathology of TSS to drive the immune response in favour of a Th17 response, and away from a Th1 response, at least in the early stages of activation [ 103 ]. There is also strong evidence that SAgs can drive the activation of the Th1 response to a pathological level [ 104 , 105 ].…”

Section: Superantigens In S Aureus Pathogenesimentioning

confidence: 99%

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Manipulation of Innate and Adaptive Immunity by Staphylococcal Superantigens

2018

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Staphylococcal superantigens (SAgs) constitute a family of potent exotoxins secreted by Staphylococcus aureus and other select staphylococcal species. SAgs function to cross-link major histocompatibility complex (MHC) class II molecules with T cell receptors (TCRs) to stimulate the uncontrolled activation of T lymphocytes, potentially leading to severe human illnesses such as toxic shock syndrome. The ubiquity of SAgs in clinical S. aureus isolates suggests that they likely make an important contribution to the evolutionary fitness of S. aureus. Although the apparent redundancy of SAgs in S. aureus has not been explained, the high level of sequence diversity within this toxin family may allow for SAgs to recognize an assorted range of TCR and MHC class II molecules, as well as aid in the avoidance of humoral immunity. Herein, we outline the major diseases associated with the staphylococcal SAgs and how a dysregulated immune system may contribute to pathology. We then highlight recent research that considers the importance of SAgs in the pathogenesis of S. aureus infections, demonstrating that SAgs are more than simply an immunological diversion. We suggest that SAgs can act as targeted modulators that drive the immune response away from an effective response, and thus aid in S. aureus persistence.

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Rapid and Rigorous IL-17A Production by a Distinct Subpopulation of Effector Memory T Lymphocytes Constitutes a Novel Mechanism of Toxic Shock Syndrome Immunopathology

Cited by 35 publications

References 94 publications

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

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

Manipulation of Innate and Adaptive Immunity by Staphylococcal Superantigens

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