title: Long-term persistence of CD4(+) but rapid disappearance of CD8(+) T cells expressing an MHC class I-restricted TCR of nanomolar affinity.
abstract: Most T cells have T cell receptors (TCR) of micromolar affinity for peptide-major histocompatibility complex (MHC) ligands, but genetic engineering can generate TCRs of nanomolar affinity. The affinity of the TCR used, m33, for its cognate non-self peptide-MHC-I complex (SIYRYYGL-K(b)) is 1,000-fold higher than of the wild-type TCR 2C. The affinity of m33 for the self-peptide dEV-8 on K(b) is only twofold higher. Mouse CD8(+) T cells transduced with an m33-encoding retrovirus showed binding of SIY-K(b) and potent function in vitro, but in vivo these T cells disappeared within hours after transfer into syngeneic hosts without causing graft-versus-host disease (GVHD). Accordingly, in cases where such CD8-dependent self-reactivity might occur in human adoptive T cell therapies, our results show that a peripheral T-cell deletion mechanism could operate to avoid reactions with the host. In contrast to CD8(+) T cells, we show that CD4(+) T cells expressing m33 survived for months in vivo. Furthermore, the m33-transduced CD4(+) T cells were able to mediate antigen-specific rejection of 6-day-old tumors. Together, we show that CD8(+) T cell expressing a MHC class I-restricted high-affinity TCR were rapidly deleted whereas CD4(+) T cells expressing the same TCR survived and provided function while being directed against a class I-restricted antigen.
authors.affiliation: Department of Pathology, Committee on Immunology, The University of Chicago, Chicago, Illinois 60637-5420, USA. bengels@bsd.uchicago.edu
authors.forename: Boris
authors.initials: B
authors.lastname: Engels
authors.forename: Adam S
authors.initials: AS
authors.lastname: Chervin
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Sant
authors.forename: David M
authors.initials: DM
authors.lastname: Kranz
authors.forename: Hans
authors.initials: H
authors.lastname: Schreiber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D009842:Oligopeptides / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology*; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D015395:Histocompatibility Antigens Class I; D009842:Oligopeptides; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C406862:superagonist SIYR