Staphylococcal Superantigens Use LAMA2 as a Coreceptor To Activate T Cells

Canonical Ag-dependent TCR signaling relies on activation of the src-family tyrosine kinase LCK. However, staphylococcal superantigens can trigger TCR signaling by activating an alternative pathway that is independent of LCK and utilizes a Gα11-containing G protein-coupled receptor (GPCR) leading to...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2018-02, Vol.200 (4), p.1471-1479
Main Authors: Li, Zhigang, Zeppa, Joseph J, Hancock, Mark A, McCormick, John K, Doherty, Terence M, Hendy, Geoffrey N, Madrenas, Joaquín
Format: Article
Language:English
Subjects:
Activation
Animals
Antagonists
Calcium
Cell activation
Enterotoxins - immunology
Enzyme-linked immunosorbent assay
Extracellular matrix
G protein-coupled receptors
Humans
Jurkat Cells
Laminin
Laminin - immunology
Lck protein
Lymphocyte Activation - immunology
Lymphocytes
Lymphocytes T
Matrix protein
Mice
Mice, Inbred C57BL
Protein-tyrosine kinase
Septic shock
Shock, Septic - immunology
Staphylococcal enterotoxin E
Staphylococcal Infections - immunology
Staphylococcus aureus - immunology
Superantigens
Superantigens - immunology
Surface plasmon resonance
T cell receptors
T-Lymphocytes - immunology
Toxic shock syndrome
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Summary:Canonical Ag-dependent TCR signaling relies on activation of the src-family tyrosine kinase LCK. However, staphylococcal superantigens can trigger TCR signaling by activating an alternative pathway that is independent of LCK and utilizes a Gα11-containing G protein-coupled receptor (GPCR) leading to PLCβ activation. The molecules linking the superantigen to GPCR signaling are unknown. Using the ligand-receptor capture technology LRC-TriCEPS, we identified LAMA2, the α2 subunit of the extracellular matrix protein laminin, as the coreceptor for staphylococcal superantigens. Complementary binding assays (ELISA, pull-downs, and surface plasmon resonance) provided direct evidence of the interaction between staphylococcal enterotoxin E and LAMA2. Through its G4 domain, LAMA2 mediated the LCK-independent T cell activation by these toxins. Such a coreceptor role of LAMA2 involved a GPCR of the calcium-sensing receptor type because the selective antagonist NPS 2143 inhibited superantigen-induced T cell activation in vitro and delayed the effects of toxic shock syndrome in vivo. Collectively, our data identify LAMA2 as a target of antagonists of staphylococcal superantigens to treat toxic shock syndrome.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1701212