Antigen-specific signaling by a soluble, dimeric peptide/major histocompatibility complex class II/Fc chimera leading to T helper cell type 2 differentiation

Interaction between a T cell receptor (TCR) and various ligands, i.e., anti -TCR antibodies, superantigens, peptides, or altered peptide ligands in the context of major histocompatibility complex (MHC) molecules can trigger di fferent T helper cell (Th) effector functions. Herein, we studied the T cel l response induced by a soluble, dimeric peptide/MHC class II chimera, name ly hemagglutinin (HA)110-120/I-E(d)alpha beta/Fc gamma 2a (DEF). We have pr eviously demonstrated that the soluble DEF molecule binds stably and specif ically to HA110-120-specific TCRs expressed by a T cell hybridoma. Administ ration of DEF in vivo induced differentiation of resting and activated pept ide-specific T cells toward a Th2 response, as indicated by the increase of interleukin (IL)-4, IL-10, and specific immunoglobulin (Ig)G1 antibodies a nd decrease of IL-2, specific IgG2a antibodies, and cytotoxic T lymphocyte activity. In contrast to HA110-120 peptide presented by the DEF molecule to T cells, the nominal synthetic peptide induced a predominant Th1 response, and the PR8 virus-derived HA110-120 peptides induced a mixed Th1/Th2 respo nse. Independent of antigen processing, soluble DEF was almost 2 logs more potent in stimulating cognate T cells than the nominal peptide. Polarizatio n of cognate T cells toward the Th2 response occurred upon interaction of s oluble DEF with TCR and CD4 molecules followed by early activation of p56(l ck) and ZAP-70 tyrosine kinases, and negative signaling of the signal trans ducer and activator of transcription (STAT)4 pathway of Th1 differentiation . DEF-like molecules may provide a new tool to study the mechanisms of sign aling toward Th2 differentiation and may also provide a potential immunothe rapeutic approach to modulate autoreactive T cells toward protective Th2 im mune responses.