The sensitivity of IL-4 production for cAMP inducers is lost in CD4+ T cells from aged mice.
CD4+ T cell clones have been demonstrated to display a differential sensitivity for the induction of cAMP. In the present study we investigated whether the differential sensitivity of CD4+ T cell clones for cAMP inducers is also applicable to freshly isolated phenotypically and functionally distinct CD4+ T cell subsets that develop naturally in aging mice. Our results show that the concanavalin A induced and anti-CD3 induced proliferative response of CD4+ T cells from young mice is more sensitive for prostaglandin E2 (PGE2) and forskolin than that of their aged counterparts, although the IL-2 production by these cells was equally sensitive. In contrast, only a slight or no inhibitory effect of these cAMP inducers was found when the cells were stimulated with the combination of phorbol myristate acetate and ionomycin. In contrast to the findings obtained with Th2 clones, IL-4 production by freshly isolated CD4+ T cells was inhibited by the cAMP inducers, whereas exogenous IL-2 had no restorative effect. However, the IL-4 production by CD4+ T cells from aged mice was less sensitive than the IL-4 production by CD4+ T cells from young mice, although CD4+ T cells from aged mice showed significantly higher levels of intracellular cAMP in response to PGE2. These higher levels of cAMP were related to the increased fraction of memory cells in aged mice: the Mel-14- Pgp-1++ CD4+ T cells responded with at least 2-fold higher levels of intracellular cAMP than the naive cells in young as well as in aged mice. Although memory CD4+ T cells from young as well as aged mice responded vigorously to PGE2 by an enhancement of intracellular cAMP, only the IL-4 production by cells from young mice was significantly inhibited. Therefore, it is not likely that the induction of cAMP is a major event in the skewing of a primary response towards a Th2 type of response.
Dobber
R
R
Section of Immunology, Institute of Aging and Vascular Research TNO, Leiden, The Netherlands.
van den Bergh
P
P
Tielemans
M
M
Schuitemaker
J
J
Nagelkerken
L
L
D000375:Aging / Q000502:physiology*; D000818:Animals; D000938:Antigen-Presenting Cells; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D003208:Concanavalin A / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D015232:Dinoprostone / Q000494:pharmacology; D004790:Enzyme Induction; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA
D007376:Interleukin-2; D003208:Concanavalin A; D005576:Colforsin; D015847:Interleukin-4; D000242:Cyclic AMP; D015232:Dinoprostone