Differential sensitivity of human naive and memory CD4+ T cells for dexamethasone.
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-CD3, (ii) immobilized anti-CD3 plus soluble anti-CD28 and (iii) soluble anti-CD2 plus soluble anti-CD28, naive CD4+ T cells appeared more sensitive to DEX than memory CD4+ T cells. In the anti-CD3 system this difference in sensitivity was apparent at a suboptimal DEX concentration. Addition of anti-CD28 rendered the cells largely insensitive to DEX, indicating 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 when naive cells were studied; in the case of memory cells, at least a 10-fold higher DEX concentration was needed to achieve a comparable inhibition. The strong inhibitory effect of DEX on naive CD4+ T cells stimulated via the alternative pathway was completely abrogated by activation of protein kinase C (PKC) with phorbol myristate acetate. Our data suggest that at least two different mechanisms contribute to DEX resistance, i.e. CD28 triggering and PKC activation, which may occur more effectively in memory cells making them less sensitive to DEX.
Nijhuis
E W
EW
Division of Immunological and Infectious Diseases, TNO Prevention and Health, Leiden, The Netherlands.
Hinloopen
B
B
van Lier
R A
RA
Nagelkerken
L
L
D018801:CD2 Antigens / Q000187:drug effects; D018106:CD28 Antigens / Q000187:drug effects; D015704:CD4 Antigens / Q000187:drug effects / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D011493:Protein Kinase C / Q000096:biosynthesis / Q000187:drug effects
D018801:CD2 Antigens; D018106:CD28 Antigens; D015704:CD4 Antigens; D003907:Dexamethasone; D011493:Protein Kinase C