Activation of CD8-dependent cytotoxic T lymphocyte adhesion and degranulation by peptide class I antigen complexes.
Activation of CTL requires engagement of both the TCR and the CD8 coreceptor. Immobilized class I proteins and in vitro-formed peptide class I Ag complexes have been used to examine the relative contributions of TCR and CD8 to the adhesion and response of cloned, class I-restricted CTL. The extent of degranulation was found to be directly proportional to the concentration of peptide used to pulse class I, suggesting that activation is a direct function of TCR occupancy level. In contrast, activation of degranulation as a function of the amount of class I on the surface displayed a marked threshold density dependence. Essentially the same density dependence was found for the response of CTL to fluid phase anti-TCR mAb and non-Ag class I, indicating that CD8-class I interaction must exceed a threshold before effective cosignaling can occur. Adhesion and degranulation of CTL was minimal in response to in vitro peptide-class I complexes prepared at a class I density below the threshold. However, the same density of peptide class I initiated both adhesion and response if additional non-Ag class I was coimmobilized on the same surface at levels above threshold. Thus, when surface levels of peptide class I complex are low, as is likely to be the case under physiologic conditions, the level of TCR occupancy achieved is, by itself, insufficient to mediate cell adhesion or activate degranulation. The results demonstrate, however, that low TCR occupancy is sufficient to provide the signal to prime CD8. Provided that the surface density of class I is sufficiently high, CD8 then mediates strong adhesion and provides the costimulatory signal(s) to activate response.
Division of Membrane Biology, Medical Biology Institute, La Jolla, CA 92037.
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016827:CD8 Antigens / Q000502:physiology*; D002448:Cell Adhesion / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D046911:Macromolecular Substances; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell