PARTIAL AGONISM AND INDEPENDENT MODULATION OF T-CELL RECEPTOR AND CD8IN HAPTEN-SPECIFIC CYTOTOXIC T-CELLS

We recently demonstrated antagonism far hapten-reactive T cells by alt ered hapten ligands. Here we investigated partial peptide- or hapten-a gonism and effects of antigen stimulation on the expression of TCR and the CD8 coreceptor using a set of DNP- or TNP-peptide-induced, H-2K(b )-restricted mouse CTL clones. Various Kb-binding TNP- and DNP-peptide s acted as partial agonists, cross-reactively stimulating individual c lones for cytotoxicity and IFN-gamma secretion, but failing to induce proliferation or TNF-alpha production. Full agonism, i.e. activation o f all possible functions, was usually restricted to those hapten-pepti de combinations used for the induction of the respective clones. Our d ata imply distinctive kinetic optima for TCR antigen contacts in the i nduction of the various T cell effector functions. Down-regulation of TCR was efficiently induced by full, but with one exception not by par tial, agonists, indicating the independence of cytotoxicity or IFN-gam ma secretion from TCR modulation. On the other hand, a reduction of TC R expression induced by full agonists was usually not accompanied by s ynchronous down-modulation of CD8 as reported by others for human T ce lls. In fact, three of four full agonists and all partial agonists mar kedly enhanced rather than reduced the expression of CD8. Increased CD 8 surface levels enhanced cytolytic potential and increased cross-reac tivity patterns of individual clones. Brefeldin A blocked this CD8 ind uction by partial agonists, and in the case of full agonists resulted in a parallel reduction of both, TCR and CD8. Thus, antigenic stimulat ion of mouse T cells initially downmodulates CD8 together with TCR, bu t the lass of coreceptor is over-compensated by a signal for increased CD8 export.