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Structural Basis of Immune Receptor Binding by Staphylococcal Superantigens

Rödström, Karin LU (2014) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2014:115.
Abstract
Superantigens (SAgs) are toxins capable of inducing a massive immune response, leading to severe disease. They are secreted by the bacteria Staphylococcus aureus and Streptococcus pyogenes, which produce the staphylococcal enterotoxins and streptococcal pyogenic exotoxins, respectively. Our immune system has evolved to protect us against foreign threats, such as bacteria and viruses. By engulfing invading pathogens, antigen-presenting cells are able to present the proteins of the pathogen as small peptides bound to major histocompatibility complexes (MHC) class II. The variable domains of a T cell receptor (TCR), situated on the surface of T cells, recognize the peptide-MHC complex, leading to clonal expansion of T cells, cytokine... (More)
Superantigens (SAgs) are toxins capable of inducing a massive immune response, leading to severe disease. They are secreted by the bacteria Staphylococcus aureus and Streptococcus pyogenes, which produce the staphylococcal enterotoxins and streptococcal pyogenic exotoxins, respectively. Our immune system has evolved to protect us against foreign threats, such as bacteria and viruses. By engulfing invading pathogens, antigen-presenting cells are able to present the proteins of the pathogen as small peptides bound to major histocompatibility complexes (MHC) class II. The variable domains of a T cell receptor (TCR), situated on the surface of T cells, recognize the peptide-MHC complex, leading to clonal expansion of T cells, cytokine secretion and immune activation. Superantigens are able to cross-link these receptors, by binding to both TCR and MHC class II simultaneously. These toxins only engage parts of the TCR, thus inducing a massive immune response, leading to illnesses such as food poisoning and toxic shock syndrome. Here, two complete TCR:SAg:MHC structures are presented, the first showing how staphylococcal enterotoxin B (SEB) engages the variable β domain of TCR and binds to the side of the MHC α-chain. Acting in a wedge-like fashion, SEB prevents TCR from reaching the peptide, thus ensuring peptide independence of the interaction. The second structure, with staphylococcal enterotoxin H (SEH), TCR and MHC class II, describes the structural manner in which SEH engages the variable α domain of TCR, contrary to all other studied superantigens. Bacterial superantigens are divided into five evolutionary groups (I-V), based on sequence similarity. They interact with immune receptors in structurally diverse ways. The X-ray structure of staphylococcal enterotoxin E (SEE), a group III SAg, in complex with TCR has been determined, along with the structure of the unbound TCR. This shows that SEE bind TCR without inducing any conformational changes in the TCR. Moreover, structures of staphylococcal enterotoxin A (SEA) and SEE in complex with the same TCR provide a basis for TRBV binding by the group III SAgs. Lastly, the superantigen SEA was shown to interact with the IL-6 signal transducer, gp130, and was also able to affect insulin signaling in adipocytes. Thus, SEA may have a potential role in type 2 diabetes, which opens a new path of superantigen biology. (Less)
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author
supervisor
opponent
  • PhD Sundberg, Eric J, University of Maryland School of Medicine, Baltimore, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Superantigen, X-ray Crystallography, T cell receptor, Major histocompatibility complex
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2014:115
pages
98 pages
publisher
Department of Experimental Medical Science, Lund Univeristy
defense location
Belfrage Hall BMC D15, Klinikgatan 32, Lund.
defense date
2014-10-17 13:00
ISSN
1652-8220
ISBN
978-91-7619-044-9
language
English
LU publication?
yes
id
4b3b951c-04a3-4fef-88fe-e2f7b760e99c (old id 4685997)
date added to LUP
2014-09-30 09:50:12
date last changed
2016-09-19 08:44:52
@phdthesis{4b3b951c-04a3-4fef-88fe-e2f7b760e99c,
  abstract     = {Superantigens (SAgs) are toxins capable of inducing a massive immune response, leading to severe disease. They are secreted by the bacteria Staphylococcus aureus and Streptococcus pyogenes, which produce the staphylococcal enterotoxins and streptococcal pyogenic exotoxins, respectively. Our immune system has evolved to protect us against foreign threats, such as bacteria and viruses. By engulfing invading pathogens, antigen-presenting cells are able to present the proteins of the pathogen as small peptides bound to major histocompatibility complexes (MHC) class II. The variable domains of a T cell receptor (TCR), situated on the surface of T cells, recognize the peptide-MHC complex, leading to clonal expansion of T cells, cytokine secretion and immune activation. Superantigens are able to cross-link these receptors, by binding to both TCR and MHC class II simultaneously. These toxins only engage parts of the TCR, thus inducing a massive immune response, leading to illnesses such as food poisoning and toxic shock syndrome. Here, two complete TCR:SAg:MHC structures are presented, the first showing how staphylococcal enterotoxin B (SEB) engages the variable β domain of TCR and binds to the side of the MHC α-chain. Acting in a wedge-like fashion, SEB prevents TCR from reaching the peptide, thus ensuring peptide independence of the interaction. The second structure, with staphylococcal enterotoxin H (SEH), TCR and MHC class II, describes the structural manner in which SEH engages the variable α domain of TCR, contrary to all other studied superantigens. Bacterial superantigens are divided into five evolutionary groups (I-V), based on sequence similarity. They interact with immune receptors in structurally diverse ways. The X-ray structure of staphylococcal enterotoxin E (SEE), a group III SAg, in complex with TCR has been determined, along with the structure of the unbound TCR. This shows that SEE bind TCR without inducing any conformational changes in the TCR. Moreover, structures of staphylococcal enterotoxin A (SEA) and SEE in complex with the same TCR provide a basis for TRBV binding by the group III SAgs. Lastly, the superantigen SEA was shown to interact with the IL-6 signal transducer, gp130, and was also able to affect insulin signaling in adipocytes. Thus, SEA may have a potential role in type 2 diabetes, which opens a new path of superantigen biology.},
  author       = {Rödström, Karin},
  isbn         = {978-91-7619-044-9},
  issn         = {1652-8220},
  keyword      = {Superantigen,X-ray Crystallography,T cell receptor,Major histocompatibility complex},
  language     = {eng},
  pages        = {98},
  publisher    = {Department of Experimental Medical Science, Lund Univeristy},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Structural Basis of Immune Receptor Binding by Staphylococcal Superantigens},
  volume       = {2014:115},
  year         = {2014},
}