Superantigen receptors

Bacterial or viral proteins linking T-cell receptors and MHC molecules through simultaneous interaction with the constant domains of all MHC class II molecules and of T-cell receptor (3-chains. Hence, superantigens are polyclonal T-cell activators most likely involved in the development of autoimmune diseases. 

The Second Step Toward Superantigen-Based Intoxication T-Cell Receptor... 

The staphylococcal superantigens initially bind to conserved elements on major histocompatibility complex class II molecules with relatively high affinity (A(i 10 mol 1 ). These receptors are found in abundance, throughout the body, on antigen-presenting cells such as macrophages and monocytes. However, each toxin... 

Finally, a recent paper by Gunther et aL shows that SEK uniquely binds to the T-cell receptor (human V/35.1) through a 15 amino-acid loop (q 3-/38) not evident in other superantigens, except for those in the same toxin grouping (e.g., SET). Surface plasmon resonance studies reveal a 6 (tmol binding affinity of SEK for V/35.1, which fits the range for other SEs when used in this technique. 

The coupling of superantigen—major histocompatibility complex class II to T-cell receptor swifdy results in cell-signaling cascades. ° These staphylococcal toxins can increase levels of phosphatidyl inositol from quiescent T cells, such as other mitogens, as well as elicit intracellular Ca movement that activates the protein kinase C (PKC) pathway important for interleukin-2 (IL-2) expression. " IL-2 is intimately linked to T-cell proliferation. In addition to the PKC pathway, the protein tyrosine kinase (PTK) pathway is also activated by superantigens, leading to elevated expression of various proinflammatory cytokines. Staphylococcal superantigens also potently activate transcriptional factors NF-/IB (nuclear factor kappa B) and AP-1 (activator protein-1), which subsequently elicit the synthesis of proinflammatory cytokines. " " ... 

Ironically, SE or TSST-1 concentrations that cause T-cell proliferation do not always correlate with receptor affinity. For instance, SEE binds HLA-DR with 100-fold lower affinity relative to the very similarly structured SEA however, SEE stimulates T-cell proliferation to equivalent levels as SEA. The dose-response curves for cytokine and chemokine production in vitro by staphylococcal superantigen-stimulated cells are also very similar despite differences in affmity/specificity for major histocompatibility complex class II and T-cell receptor V/3 molecules. Overall, these observations suggest that the biological effects of staphylococcal superantigens are induced at rather low, nonsaturating occupancy rates not readily classified by typical biokinetics. 

Li H, Llera A, Mariuzza RA. 1998. Structure function studies of T cell receptor-superantigen interactions. Immunol Rev. 163 177-186. 

Streptococcus pyogenes and Staphylococcus aureus secrete a number of enterotoxins and pyrogenic exotoxins, respectively. These toxins are known as superantigens, since they simultaneously form complexes with the major histocompatibility class II (MHC-II) molecules and T-cell receptors (TCRs) enabling them to activate a number of T-cell lymphocytes. Thus, superantigens stimulate up to... 

Mingari MC, Ponte M, Bertone S, Schiavetti F, Vitale C, BeUomo R, Moretta A, Moretta L (1998) HLA class I-specilic inhibitory receptors in human T lymphocytes Interleukin 15-induced expression of CD94/ NKG2A in superantigen- or aUoantigen-activaled CD8-I- T cells. Proc Natl Acad Sd USA 95 1172-1177. 

Figure 7-1 Activation of T cells by metal ions. Nickel and other metal ions appear to activate specific T cells by several different molecular mechanisms. (1) T cells with their T cell receptor respond to complexes of nickel with MHC-peptide similar to other hapten-peptide complexes. (2) Nickel forms a direct linker between MHC and the T cell receptor independent of the peptide with some similarities to superantigen-mediated T cell stimulation. (3) The processing of self peptides is disturbed by nickel resulting in cryptic self peptides presented to a T cell receptor.

Most exotoxins fall into one of three categories on the basis of their structure and activities. These are the A-B toxins, the cytolytic toxins and the superantigen toxins. The A-B toxins consist of a B subunit that binds to a host cell receptor, covalently bound to the A subunit that mediates the enzymic activity responsible for toxicity. Most exotoxins (e.g. diphtheria toxin, cholera toxin) are of the A-B category. The cytolytic toxins such as haemolysins and phospholipases do not have separable A and B... 

Molecular Interactions of Superantigens with Receptor Molecules... 

Seth A, Stem LJ, OttenhofFTH, Engel I, Owen MJ, Lamb JR, Klausner RD, Wiley DC Binary and ternary complexes between T-cell receptor, class II MHC and superantigen in vitro. Nature 1994 369 324-327. 

Choi YW, Herman A, DiGiusto D, Wade T, Marrack P, Kappler J Residues of the variable region of the T-cell-receptor beta-chain that interact with S. aureus toxin superantigens. Nature 1990 346 471 173. 

Papageorgiou AC, Collins CM, Gutman DM, Kline JB, O Brian SM, Tranter HS, Acharya KR Structural basis for the recognition of superantigen streptococcal pyrogenic exotoxin A (SpeA) by MHC class II molecules and T cell receptors. EMBO J 1999 18 9-21. 

De Marzi M, Fernandez M, Sundbeig E, Molinero L, Zwimer N, Llera A, Mariuzza R, Malchiodi E Cloning, expression, and interaction of human T cell receptors with the bacterial superantigen SSA. Eur J Biochem 2004 271 4075 1083. 

Li H, Llera A, Tsuchiya D, Leder L, Ysem X, Schlievert PM, Karjalainen K, Mariuzza RA Three-dimensional structure of the complex between a T cell receptor beta chain and the superantigen staphylococcal enterotoxin B. Immunity 1998 9 807-816. 

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