Soluble T cell receptor Vβ domains engineered for high-affinity binding to staphylococcal or streptococcal superantigens

Preeti Sharma, Ningyan Wang, David M. Kranz

Research output: Contribution to journalReview article

Abstract

Staphylococcus aureus and group A Streptococcus secrete a collection of toxins called superantigens (SAgs), so-called because they stimulate a large fraction of an individual's T cells. One consequence of this hyperactivity is massive cytokine release leading to severe tissue inflammation and, in some cases, systemic organ failure and death. The molecular basis of action involves the binding of the SAg to both a T cell receptor (TCR) on a T cell and a class II product of the major histocompatibility complex (MHC) on an antigen presenting cell. This cross-linking leads to aggregation of the TCR complex and signaling. A common feature of SAgs is that they bind with relatively low affinity to the variable region (V) of the beta chain of the TCR. Despite this low affinity binding, SAgs are very potent, as each T cell requires only a small fraction of their receptors to be bound in order to trigger cytokine release. To develop high-affinity agents that could neutralize the activity of SAgs, and facilitate the development of detection assays, soluble forms of the Vβ regions have been engineered to affinities that are up to 3 million-fold higher for the SAg. Over the past decade, six different Vβ regions against SAgs from S. aureus (SEA, SEB, SEC3, TSST-1) or S. pyogenes (SpeA and SpeC) have been engineered for high-affinity using yeast display and directed evolution. Here we review the engineering of these high-affinity Vβ proteins, structural features of the six different SAgs and the Vβ proteins, and the specific properties of the engineered Vβ regions that confer high-affinity and specificity for their SAg ligands.

Original languageEnglish (US)
Pages (from-to)556-574
Number of pages19
JournalToxins
Volume6
Issue number2
DOIs
StatePublished - Feb 13 2014

Fingerprint

Superantigens
T-Cell Antigen Receptor
T-cells
T-Lymphocytes
Staphylococcus aureus
Cytokines
Antigen Receptors, T-Cell, alpha-beta
Antigen-Presenting Cells
Streptococcus
Major Histocompatibility Complex
Yeast
Assays
Proteins
Agglomeration
Yeasts
Display devices
Tissue
Ligands
Inflammation

Keywords

  • Affinity maturation
  • Complementarity determining regions
  • Directed evolution
  • Framework regions
  • Superantigens
  • T-cell receptor
  • Yeast display

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Soluble T cell receptor Vβ domains engineered for high-affinity binding to staphylococcal or streptococcal superantigens. / Sharma, Preeti; Wang, Ningyan; Kranz, David M.

In: Toxins, Vol. 6, No. 2, 13.02.2014, p. 556-574.

Research output: Contribution to journalReview article

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