Antigen-specific CD8+ T cells mediate a peptide-induced fatal syndrome.
Peptide immunotherapy both activates and suppresses the T cell response against known peptide Ags. Although pretreatment with VP2(121-130) peptide inhibits the development of antiviral CTL specific for the immunodominant D(b):VP2(121-130) epitope expressed during acute Theiler's murine encephalomyelitis virus infection, i.v. injection of this same peptide or MHC tetramers containing the peptide during an ongoing antiviral CTL response results in a peptide-induced fatal syndrome (PIFS) within 48 h. Susceptibility to PIFS is dependent on peptide-specific CD8(+) T cells, varies among inbred strains of mice, and is not mediated by traditionally defined mechanisms of shock. Analyses using bone marrow chimeras and mutant mice demonstrate that susceptibility to PIFS is determined by the genotype of bone marrow-derived cells and requires the expression of perforin. Animals responding to peptide treatment with PIFS develop classical stress responses in the brain. These findings raise important considerations for the development of peptide therapies for active diseases to modify immune responses involving expanded populations of T cells. In summary, treatment with peptides or MHC-tetramers during a peptide-specific immune response can result in a fatal shock-like syndrome. Susceptibility to the syndrome is genetically determined, is mediated by CD8(+) T cells, and requires expression of perforin. These findings raise concerns about the use of peptides and MHC tetramers in therapeutic schemes.
Johnson
Aaron J
AJ
Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Mendez-Fernandez
Yanice
Y
Moyer
Ann M
AM
Sloma
Cari R
CR
Pirko
Istvan
I
Block
Matthew S
MS
Rodriguez
Moses
M
Pease
Larry R
LR
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002199:Capillary Permeability / Q000235:genetics / Q000276:immunology; D036022:Capsid Proteins / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D018188:Cardiovirus Infections / Q000235:genetics / Q000276:immunology* / Q000401:mortality* / Q000503:physiopathology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006183:H-2 Antigens / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000502:physiology; D007113:Immunity, Innate / Q000235:genetics; D007115:Immunization Schedule; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D013577:Syndrome; D017945:Theilovirus / Q000276:immunology*; D000096743:Interferon gamma Receptor
D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C442556:VP2 protein, Theilovirus