DIFFERENTIAL SENSITIVITY OF HUMAN NAIVE AND MEMORY CD4(-CELLS FOR DEXAMETHASONE() T)

Human CD45RA(+) ('naive') and CD45RO(+) ('memory') CD4(+) T cells were compared with respect to their sensitivity to dexamethasone (DEX). In three different activation pathways, i.e. (i) immobilized anti-CDS, ( ii) immobilized anti-CD3 plus soluble anti-CD28 and (iii) soluble anti -CDS plus soluble anti-CD28 naive CD4(+) T cells appeared more sensiti ve to DEX than memory CD4(+) T cells. In the anti-CD3 system this diff erence in sensitivity was apparent at a suboptimal DEX concentration. Addition of anti-CD28 rendered the cells largely insensitive to DEX, i ndicating that the CD28 pathway is less dependent of the DEX-sensitive transcription factor AP-1. However, the alternative pathway of T cell activation through CD2/CD28 triggering was highly sensitive to DEX wh en naive cells were studied; in the case of memory cells, at least a 1 0-fold higher DEX concentration was needed to achieve a comparable inh ibition. The strong inhibitory effect of DEX on naive CD4(+) T cells s timulated via the alternative pathway was completely abrogated by acti vation of protein kinase C (PKC) with phorbol myristate acetate. Our d ata suggest that at least two different mechanisms contribute to DEX r esistance, i.e. CD28 triggering and PKC activation, which may occur mo re effectively in memory cells making them less sensitive to DEX.