Invariant NKT cells are pathogenic in the HLA-DR4-transgenic humanized mouse model of toxic shock syndrome and can be targeted to reduce morbidity

Szabo, Peter A.; Rudak, Patrick T.; Choi, Joshua J.; Xu, Shuai; Schaub, Robert G.; Singh, Bhagirath; McCormick, John K.; Haeryfar, S. M. Mansour

doi:10.1093/infdis/jiw646

Cited by 14 publications

(18 citation statements)

References 15 publications

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“…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 ].…”

Section: Bacterial Immune Evasion Strategiesmentioning

confidence: 99%

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

Shepherd

McLaren

2020

IJMS

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The human body frequently encounters harmful bacterial pathogens and employs immune defense mechanisms designed to counteract such pathogenic assault. In the adaptive immune system, major histocompatibility complex (MHC)-restricted αβ T cells, along with unconventional αβ or γδ T cells, respond to bacterial antigens to orchestrate persisting protective immune responses and generate immunological memory. Research in the past ten years accelerated our knowledge of how T cells recognize bacterial antigens and how many bacterial species have evolved mechanisms to evade host antimicrobial immune responses. Such escape mechanisms act to corrupt the crosstalk between innate and adaptive immunity, potentially tipping the balance of host immune responses toward pathological rather than protective. This review examines the latest developments in our knowledge of how T cell immunity responds to bacterial pathogens and evaluates some of the mechanisms that pathogenic bacteria use to evade such T cell immunosurveillance, to promote virulence and survival in the host.

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Section: Bacterial Immune Evasion Strategiesmentioning

confidence: 99%

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

Shepherd

McLaren

2020

IJMS

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“…Generally, SAgs have weak affinity for murine MHC class II molecules compared to human HLA molecules [ 97 ]. Using transgenic animals such as the C57BL/6 DR4tg that express the human DR4 HLA allele, SAg mediated disease such as TSS can be modelled as these animals become significantly more sensitive to direct exposure to purified SAgs such as SEB [ 98 ]. These animals can also be utilized in a bacteremia model for SAg expressing strains of S. aureus .…”

Section: Superantigens In S Aureus Pathogenesimentioning

confidence: 99%

“…Considerable efforts have focused on understanding the stimulation of conventional (i.e., MHC-restricted CD4 + and CD8 + ) T cells; however, ‘unconventional’ T cells that harbor unique TCRs also represent important components of the human immune system. These include CD1d-restricted natural killer T (NKT) cells, mucosa-associated invariant T (MAIT) cells and γδ T cells, each of which appear to be activated directly or indirectly by SAgs ( Figure 2 ) [ 98 , 133 , 134 ]. Unconventional T cells, in general, express a less variable TCR compared to conventional T cells, and have rapid effector responses once stimulated.…”

Section: Superantigens In S Aureus Pathogenesimentioning

confidence: 99%

“…SEB that targets mouse Vβ8), can directly activate i NKT cells and therefore can alter the host cytokine profile in an i NKT cell-dependent manner [ 134 ]. Indeed, HLA-DR4 transgenic mice depleted of i NKT were significantly less susceptible to challenge with SEB [ 98 ]. In this work, i NKT cells were important for production of an early wave of cytokines, including IL-17A and IFNγ, which triggered severe inflammation in mice with functioning i NKT cells [ 98 ].…”

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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“…Activation of these cell types by SEs can have a considerable impact on the immune system, which may lead to non-conventional overstimulation of the immune system, as exemplified by B cell proliferation and differentiation into plasma cells (Stohl et al, 1994 ). Additionally, excessive inflammation, as a result of the direct activation of i NKT cells and γδ T cells, can cause the production of SE-associated inflammatory disease in the lungs (Rieder et al, 2011 ) and systemic infection, as demonstrated in mouse infection models (Szabo et al, 2017 ).…”

Section: The Enterotoxins Are Immunomodulators Of Multiple Immune Celmentioning

confidence: 99%

Basis of Virulence in Enterotoxin-Mediated Staphylococcal Food Poisoning

2018

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The Staphylococcus aureus enterotoxins are a superfamily of secreted virulence factors that share structural and functional similarities and possess potent superantigenic activity causing disruptions in adaptive immunity. The enterotoxins can be separated into two groups; the classical (SEA-SEE) and the newer (SEG-SElY and counting) enterotoxin groups. Many members from both these groups contribute to the pathogenesis of several serious human diseases, including toxic shock syndrome, pneumonia, and sepsis-related infections. Additionally, many members demonstrate emetic activity and are frequently responsible for food poisoning outbreaks. Due to their robust tolerance to denaturing, the enterotoxins retain activity in food contaminated previously with S. aureus. The genes encoding the enterotoxins are found mostly on a variety of different mobile genetic elements. Therefore, the presence of enterotoxins can vary widely among different S. aureus isolates. Additionally, the enterotoxins are regulated by multiple, and often overlapping, regulatory pathways, which are influenced by environmental factors. In this review, we also will focus on the newer enterotoxins (SEG-SElY), which matter for the role of S. aureus as an enteropathogen, and summarize our current knowledge on their prevalence in recent food poisoning outbreaks. Finally, we will review the current literature regarding the key elements that govern the complex regulation of enterotoxins, the molecular mechanisms underlying their enterotoxigenic, superantigenic, and immunomodulatory functions, and discuss how these activities may collectively contribute to the overall manifestation of staphylococcal food poisoning.

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Invariant NKT cells are pathogenic in the HLA-DR4-transgenic humanized mouse model of toxic shock syndrome and can be targeted to reduce morbidity

Cited by 14 publications

References 15 publications

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

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

Manipulation of Innate and Adaptive Immunity by Staphylococcal Superantigens

Basis of Virulence in Enterotoxin-Mediated Staphylococcal Food Poisoning

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