Design of Chimeric Receptor Mimics with Different TcRVβ Isoforms

• Published in: The Journal of biological chemistry Vol. 279; no. 7; p. 5676
• Main Authors: Elizabeth Hong-Geller, Margit Möllhoff, Patrick R. Shiflett, Goutam Gupta
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 13-02-2004
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M309388200

The Staphylococcus aureus enterotoxins (S.E.) A-I, and toxic-shock syndrome toxin TSST-1 act as superantigens to cause overstimulation of the host
immune system, leading to the onset of various diseases including food poisoning and toxic shock syndrome. SAgs bind as intact
proteins to the DRα1 domain of the MHC class II receptor and the TcRVβ domain from the T cell receptor and cause excessive
release of cytokines such as IL-2, TNF-α, and IFN-γ, and hyperproliferation of T cells. In addition, different SAgs bind and
activate different TcRVβ isoforms during pathogenesis of human immune cells. These two properties of SAgs prompted us to design
several chimeric DRα1-linker-TcRVβ proteins using different TcRVβ isoforms to create chimeras that would specifically inhibit
the pathogenesis of SAgs against which they were designed. In this study, we compare the design, interaction, and inhibitory
properties of three different DRα1-linker-TcRVβ chimeras targeted against three different SAgs, SEB, SEC3, and TSST-1. The
inhibitory properties of the chimeras were tested by monitoring IL-2 release and T cell proliferation using a primary human
cell model. We demonstrate that the three chimeras specifically inhibit the pathogenesis of their target superantigen. We
performed molecular modeling to analyze the structural basis of the type specificity exhibited by different chimeras designed
against their target SAgs, examine the role of the linker in determining binding and specificity, and suggest site-specific
mutations in the chimera to enhance binding affinity. The fact that our strategy works equally well for SEB and TSST-1, two
widely different phylogenic variants, suggests that the DRα1-linker-TcRVβ chimeras may be developed as a general therapy against
a broad spectrum of superantigens released during Staphylococcal infection.