Selective deletion of antigen-specific CD8+ T cells by MHC class I tetramers coupled to the type I ribosome-inactivating protein saporin.
CD8+ cytotoxic T lymphocytes (CTLs) are important effector cells responsible for tissue destruction in several autoimmune and allograft-related diseases. To discover if pathogenic T cells could be selectively deleted, we investigated the ability of a toxin coupled to major histocompatibility complex (MHC) class I tetramers to kill antigen-specific CD8+ T cells. H2-D(b) tetramers were assembled using streptavidin conjugated to the ribosome-inactivating protein (RIP) saporin (SAP). These tetramers inhibited ribosome activity in vitro, retained the T-cell receptor (TCR)-binding specificity of their nontoxic counterparts, and were internalized by 100% of target cells, leading to cell death in 72 hours. Cytotoxicity was dependent on the tetramer dose and avidity for the T cell. A single injection of the SAP-coupled tetramer eliminated more than 75% of cognate, but not control, T cells. This work demonstrates the therapeutic potential of cytotoxic tetramers to selectively eradicate pathogenic clonotypes while leaving overall T-cell immunity intact.
Hess
Paul R
PR
Department of Microbiology and Immunology, Universaity of North Carolina, Chapel Hill, NC, USA. paul_hess@ncsu.edu
Barnes
Carie
C
Woolard
Matthew D
MD
Johnson
Michael D L
MD
Cullen
John M
JM
Collins
Edward J
EJ
Frelinger
Jeffrey A
JA
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D017637:Clonal Deletion / Q000187:drug effects*; D003603:Cytotoxins / Q000276:immunology / Q000494:pharmacology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009699:N-Glycosyl Hydrolases / Q000494:pharmacology*; D010940:Plant Proteins / Q000494:pharmacology*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013997:Time Factors; D014184:Transplantation, Homologous
D003603:Cytotoxins; D015395:Histocompatibility Antigens Class I; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; D000076985:Saporins