Limited in vivo reactivity of polyclonal effector cytotoxic T cells towards altered peptide ligands.
T cell responses are regulated by the affinity/avidity of the T cell receptor for the MHC/peptide complex, available costimulation and duration of antigenic stimulation. Altered peptide ligands (APLs) are usually recognized with a reduced affinity/avidity by the T cell receptor and are often able to only partially activate T cells in vitro or may even function as antagonists. Here we assessed the ability of APLs derived from peptide p33 of lymphocytic choriomeningitis virus (LCMV) to mediate lysis of target cells in vivo, confer anti-viral protection and cause auto-immune disease. In general, in vitro cross-reactivity between APLs was rather limited, and even strongly cross-reactive cytotoxic T lymphocytes were only able to mediate moderate anti-viral protection. Partial protection was observed for infection with LCMV or low doses of recombinant vaccinia virus, while no reduced viral titers could be seen upon infection with high dose of vaccinia virus. In a transgenic mouse model expressing LCMV glycoprotein in the islets of the pancreas, APLs induced a transient insulitis but failed to induce autoimmune diabetes. Thus, effector functions induced by even highly homologous APLs are rather limited in vivo.
Bättig
Patrick
P
Cytos Biotechnology, AG Wagistrasse 25, 8952 Zürich-Schlieren, Switzerland.
Saudan
Philippe
P
Storni
Tazio
T
Gallimore
Awen
A
Bachmann
Martin F
MF
D000818:Animals; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D003429:Cross Reactions; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects*; D008216:Lymphocytic Choriomeningitis / Q000150:complications / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*
D000956:Antigens, Viral; D006023:Glycoproteins; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus