Partial agonism and independent modulation of T cell receptor and CD8 in hapten-specific cytotoxic T cells.
We recently demonstrated antagonism for hapten-reactive T cells by altered hapten ligands. Here we investigated partial peptide- or hapten-agonism and effects of antigen stimulation on the expression of TCR and the CD8 coreceptor using a set of DNP- or TNP-peptide-induced, H-2Kb-restricted mouse CTL clones. Various Kb-binding TNP- and DNP-peptides acted as partial agonists, cross-reactively stimulating individual clones for cytotoxicity and IFN-gamma secretion, but failing to induce proliferation or TNF-alpha production. Full agonism, i.e. activation of all possible functions, was usually restricted to those hapten-peptide combinations used for the induction of the respective clones. Our data imply distinctive kinetic optima for TCR antigen contacts in the induction of the various T cell effector functions. Down-regulation of TCR was efficiently induced by full, but with one exception not by partial, agonists, indicating the independence of cytotoxicity or IFN-gamma secretion from TCR modulation. On the other hand, a reduction of TCR expression induced by full agonists was usually not accompanied by synchronous down-modulation of CD8 as reported by others for human T cells. In fact, three of four full agonists and all partial agonists markedly enhanced rather than reduced the expression of CD8. Increased CD8 surface levels enhanced cytolytic potential and increased cross-reactivity patterns of individual clones. Brefeldin A blocked this CD8 induction by partial agonists, and in the case of full agonists resulted in a parallel reduction of both, TCR and CD8. Thus, antigenic stimulation of mouse T cells initially down-modulates CD8 together with TCR, but the loss of coreceptor is over-compensated by a signal for increased CD8 export.
Preckel
T
T
Max-Planck-Institut für Immunbiologie, Freiburg, Germany.
Breloer
M
M
Kohler
H
H
von Bonin
A
A
Weltzien
H U
HU
D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D016827:CD8 Antigens / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D006241:Haptens / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D016827:CD8 Antigens; D016207:Cytokines; D006241:Haptens; D011948:Receptors, Antigen, T-Cell; D020126:Brefeldin A; D003513:Cycloheximide