Antigen-Specific Signaling by a Soluble, Dimeric Peptide/Major Histocompatibility Complex Class II/Fc Chimera Leading to T Helper Cell Type 2 Differentiation

doi:10.1084/jem.190.4.543

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© The Rockefeller University Press, 0022-1007/1999/8/543/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 4, August 16, 1999 543-554

Original Article

Antigen-Specific Signaling by a Soluble, Dimeric Peptide/Major Histocompatibility Complex Class II/Fc Chimera Leading to T Helper Cell Type 2 Differentiation

Sofia Casares^a, Cong S. Zong^a, Dorel L. Radu^a, Alexander Miller^a, Constantin A. Bona^a, and Teodor-Doru Brumeanu^a

^a From the Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029
Dept. of Microbiology, Mount Sinai School of Medicine, 1 Gustave L. Levy Pl., New York, NY 10029.212-828-4151212-241-7551

brumet01{at}doc.mssm.edu

Interaction between a T cell receptor (TCR) and various ligands,i.e., anti-TCR antibodies, superantigens, peptides, or alteredpeptide ligands in the context of major histocompatibility complex(MHC) molecules can trigger different T helper cell (Th) effectorfunctions. Herein, we studied the T cell response induced bya soluble, dimeric peptide/MHC class II chimera, namely hemagglutinin(HA)110-120/I-E^d ${alpha}$ β/Fc ${gamma}$ 2a (DEF). We have previously demonstratedthat the soluble DEF molecule binds stably and specificallyto HA110-120–specific TCRs expressed by a T cell hybridoma.Administration of DEF in vivo induced differentiation of restingand activated peptide-specific T cells toward a Th2 response,as indicated by the increase of interleukin (IL)-4, IL-10, andspecific immunoglobulin (Ig)G1 antibodies and decrease of IL-2,specific IgG2a antibodies, and cytotoxic T lymphocyte activity.In contrast to HA110-120 peptide presented by the DEF moleculeto T cells, the nominal synthetic peptide induced a predominantTh1 response, and the PR8 virus–derived HA110-120 peptidesinduced a mixed Th1/Th2 response. Independent of antigen processing,soluble DEF was almost 2 logs more potent in stimulating cognateT cells than the nominal peptide. Polarization of cognate Tcells toward the Th2 response occurred upon interaction of solubleDEF with TCR and CD4 molecules followed by early activationof p56^lck and ZAP-70 tyrosine kinases, and negative signalingof the signal transducer and activator of transcription (STAT)4pathway of Th1 differentiation. DEF-like molecules may providea new tool to study the mechanisms of signaling toward Th2 differentiationand may also provide a potential immunotherapeutic approachto modulate autoreactive T cells toward protective Th2 immuneresponses.

Key Words: Th2 differentiation • peptide/MHC II chimera • STAT proteins

1used in this paper: HA, hemagglutinin; HRP, horseradish peroxidase;STATs, signal transducers and activators of transcription; TcH,T cell hybridoma; Tg, transgenic

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