Staphylococcal Superantigens Use LAMA2 as a Coreceptor To Activate T Cells

Li, Zhigang; Zeppa, Joseph J.; Hancock, Mark A.; McCormick, John K.; Doherty, Terence M.; Hendy, Geoffrey N.; Madrenas, Joaquı́n

doi:10.4049/jimmunol.1701212

Cited by 14 publications

(13 citation statements)

References 53 publications

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“…Alongside TCR/MHC Class II activation, signalling pathways are co-stimulated by crosslinking CD28 on the T-cell with CD80/B7-2 on APCs ( 53 – 56 ). T-cell superantigens can also crosslink the α-subunit of laminin, LAMA2, with G-protein coupled receptor (GPCR), resulting in T-cell stimulation ( 57 – 59 ) ( Figure 2 ).…”

Section: Cellular Responses To T-cell Superantigensmentioning

confidence: 99%

Superantigen Recognition and Interactions: Functions, Mechanisms and Applications

2021

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Superantigens are unconventional antigens which recognise immune receptors outside their usual recognition sites e.g. complementary determining regions (CDRs), to elicit a response within the target cell. T-cell superantigens crosslink T-cell receptors and MHC Class II molecules on antigen-presenting cells, leading to lymphocyte recruitment, induction of cytokine storms and T-cell anergy or apoptosis among many other effects. B-cell superantigens, on the other hand, bind immunoglobulins on B-cells, affecting opsonisation, IgG-mediated phagocytosis, and driving apoptosis. Here, through a review of the structural basis for recognition of immune receptors by superantigens, we show that their binding interfaces share specific physicochemical characteristics when compared with other protein-protein interaction complexes. Given that antibody-binding superantigens have been exploited extensively in industrial antibody purification, these observations could facilitate further protein engineering to optimize the use of superantigens in this and other areas of biotechnology.

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Section: Cellular Responses To T-cell Superantigensmentioning

confidence: 99%

Superantigen Recognition and Interactions: Functions, Mechanisms and Applications

2021

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“…There is also data to suggest that SAgs can also bind the costimulatory molecule CD28 and it co-ligand B7-2 contributing to the hyperactivity of the stimulated T cell [ 18 , 19 ]. Additionally, SAgs can activate T cells in a manner that is independent of the tyrosine kinase Lck [ 20 ], and recently this alternative T cell activation pathway has been linked to the α2 subunit of the extracellular matrix protein laminin (LAMA2), acting as a SAg co-receptor [ 21 ]. With the noted exception of staphylococcal enterotoxin H (SEH), which is a Vα-specific SAg [ 22 ], characterized SAgs each interact with the Vβ chain of the TCR resulting in stimulation of up to ~20% of the T cell population [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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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“…Conceptually, the target can then be identified through MS analysis. Although this elegant ligand-based receptor-capture (LRC) strategy has resulted in successful identification of certain membrane receptors (Li et al, 2016, 2018; Ponda and Breslow, 2016), identification can only occur for receptors carrying an N-linked glycan in close proximity to the ligand-binding site. To overcome this glycan dependency, others have recently developed ligand-derived probes harboring photoaffinity labels to capture target receptors (Blex et al, 2017; Thomas et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of a Diazirine Photoaffinity Probe for Ligand-Based Receptor Capture Targeting G Protein–Coupled Receptors

et al. 2018

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Chemoproteomic approaches to identify ligand-receptor interactions have gained popularity. However, identifying transmembrane receptors remains challenging. A new trifunctional probe to aid the nonbiased identification of such receptors was developed and synthesized using a convenient seven-step synthesis. This probe contained three functional groups: 1) an N-hydroxysuccinimide ester for ligand-coupling through free amines, 2) a diazirine moiety to capture the receptor of interest upon irradiation with UV light, and 3) a biotin group which allowed affinity purification of the final adduct using streptavidin. The interaction between the G protein–coupled tachykinin neurokinin 1 (NK1) receptor, expressed in an inducible manner, and the peptidic ligand substance P was used as a test system. Liquid chromatography–mass spectrometry analysis confirmed successful coupling of the probe to substance P, while inositol monophosphate accumulation assays demonstrated that coupling of the probe did not interfere substantially with the substance P–NK1 receptor interaction. Confocal microscopy and western blotting provided evidence of the formation of a covalent bond between the probe and the NK1 receptor upon UV activation. As proof of concept, the probe was used in full ligand-based receptor-capture experiments to identify the substance P–binding receptor via liquid chromatography–tandem mass spectrometry, resulting in the successful identification of only the NK1 receptor. This provides proof of concept toward general utilization of this probe to define interactions between ligands and previously unidentified plasma-membrane receptors.

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Staphylococcal Superantigens Use LAMA2 as a Coreceptor To Activate T Cells

Cited by 14 publications

References 53 publications

Superantigen Recognition and Interactions: Functions, Mechanisms and Applications

Superantigen Recognition and Interactions: Functions, Mechanisms and Applications

Manipulation of Innate and Adaptive Immunity by Staphylococcal Superantigens

Design, Synthesis, and Evaluation of a Diazirine Photoaffinity Probe for Ligand-Based Receptor Capture Targeting G Protein–Coupled Receptors

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