Chimeric beta2 microglobulin/CD3zeta polypeptides expressed in T cells convert MHC class I peptide ligands into T cell activation receptors: a potential tool for specific targeting of pathogenic CD8(+) T cells.
CD8(+) T cells are key mediators of transplant rejection and graft-versus-host disease and contribute to the pathogenesis of autoimmune diseases. We tested whether TCR ligands can be converted into T cell activation receptors, redirecting genetically modified T cells at pathogenic CD8(+) T cells. For this purpose we exploited the ability of the non-polymorphic beta(2) microglobulin light chain to pair with all MHC class I heavy chains. In this report we describe the design and expression in a T cell hybridoma of two modalities of beta(2) microglobulin polypeptides, fused with the transmembrane and intracellular portion of CD3zeta chain. In the absence of a particular antigenic peptide, the chimeric product associates with different endogenous MHC class I heavy chains and triggers T cell activation upon heavy chain cross-linking. When an antigenic peptide is covalently attached to the N-terminus of the chimeric polypeptide, transfectants express high level of surface peptide-class I complexes and respond to antibodies and target T cells in a peptide-specific manner. Our results provide the basis for a universal genetic approach aimed at antigen-specific immunotargeting of pathogenic CD8(+) T cells.
Margalit
Alon
A
MIGAL, Galilee Technology Center, South Industrial Zone, Kiryat Shmona 11016, Israel.
Fishman
Sigal
S
Berko
Dikla
D
Engberg
Jan
J
Gross
Gideon
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005822:Genetic Vectors; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007154:Immune System Diseases / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D010957:Plasmids; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D001613:beta 2-Microglobulin