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J. Biol. Chem., Vol. 279, Issue 7, 5676-5684, February 13, 2004

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Design of Chimeric Receptor Mimics with Different TcRV Isoforms

TYPE-SPECIFIC INHIBITION OF SUPERANTIGEN PATHOGENESIS^*

Elizabeth Hong-Geller, Margit Möllhoff, Patrick R. Shiflett, and Goutam Gupta

From the Los Alamos National Laboratory, Biosciences Division, HRL-1, MS-M888, Los Alamos, New Mexico 87544

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 DR1 domain of the MHC class II receptor and the TcRV domain from the T cell receptor and cause excessive release of cytokines such as IL-2, TNF-, and IFN-, and hyperproliferation of T cells. In addition, different SAgs bind and activate different TcRV isoforms during pathogenesis of human immune cells. These two properties of SAgs prompted us to design several chimeric DR1-linker-TcRV proteins using different TcRV 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 DR1-linker-TcRV 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 DR1-linker-TcRV chimeras may be developed as a general therapy against a broad spectrum of superantigens released during Staphylococcal infection.

Received for publication, August 25, 2003

^* This work was funded by the Department of Energy and by Los Alamos National Laboratory Directed Research and Development (to G. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 505-663-5118; Fax: 505-665-3024; E-mail: gxg{at}lanl.gov.

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