Parenchymal cells critically curtail cytotoxic T-cell responses by inducing Bim-mediated apoptosis.
To develop cytolytic effector functions, CD8(+) T lymphocytes need to recognize specific Ag/MHC class I complexes in the context of costimuli on Ag-presenting DC. Thereafter they differentiate into effector and memory CTL able to confer protection against pathogen infection. Using transgenic mice with DC-selective MHC class I expression and DC-specific versus ubiquitous vaccination regimen, we found that DC are sufficient to prime CTL responses. However, Ag recognition on parenchymal non-professional APC negatively affected CD8(+) T-cell responses in mice by inducing expression of the pro-apoptotic bcl2-family member bim in CTL. This unexpected induction of apoptosis in the early phase of effector CTL accumulation lead to suboptimal clonal burst size and diminished long-term memory. Thus, our data demonstrate that effector CTL differentiation and apoptosis are regulated independently. Moreover, Ag distribution on cells other than DC critically reduces CTL responses.
Gruber
Anton
A
Institute for Immunology, Ludwig-Maximilians-University, Munich, Germany.
Cannarile
Michael A
MA
Cheminay
Cedric
C
Ried
Christine
C
Marconi
Peggy
P
Häcker
Georg
G
Brocker
Thomas
T
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006183:H-2 Antigens / Q000276:immunology; D007156:Immunologic Memory; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011994:Recombinant Proteins / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D014611:Vaccination
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D006183:H-2 Antigens; D008565:Membrane Proteins; C110366:OVA-8; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D018664:Interleukin-12; D010047:Ovalbumin