Escape of thymocytes and mature T cells from clonal deletion due to limiting tolerogen expression levels.
Expression of self antigen on lymphohemopoietic cells and in the thymus has been shown to cause tolerance by negative selection. To investigate the role of self antigen expression levels on the induction of tolerance, we generated transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) driven by the H-2Kb promoter. Two mouse lines differing in transgene expression levels were obtained and evaluated for the induction of tolerance to LCMV-GP. LCMV-GP high (GPhi) expressing animals thymically deleted self-reactive thymocytes. Low expressors (GPlo) partially deleted self-reactive mature T cells in the periphery in the absence of any obvious signs of negative selection in the thymus. Functionally, the LCMV-GP-specific cytotoxic T cell (CTL) response was absent in GPhi mice, whereas GPlo mice produced diminished LCMV-GP-specific CTL responses. Therefore limiting levels of expression of self antigen influence efficiency of negative selection, enabling potentially self-reactive T cells to escape from tolerance induction.
Oehen
S U
SU
Institut für Experimentelle Immunologie, University Hospital Zürich, Switzerland.
Ohashi
P S
PS
Bürki
K
K
Hengartner
H
H
Zinkernagel
R M
RM
Aichele
P
P
D000818:Animals; D016026:Bone Marrow Transplantation; D017637:Clonal Deletion / Q000502:physiology*; D003601:Cytotoxicity Tests, Immunologic; D005434:Flow Cytometry; D006023:Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011828:Radiation Chimera / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology*; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000096:biosynthesis / Q000276:immunology
D006023:Glycoproteins; D014764:Viral Proteins