Disparate effects of phorbol esters, CD3 and the costimulatory receptors CD2 and CD28 on RANTES secretion by human T lymphocytes.

Publisher: Blackwell Scientific Publications Country of Publication: England NLM ID: 0374672 Publication Model: Print Cited Medium: Print ISSN: 0019-2805 (Print) Linking ISSN: 00192805 NLM ISO Abbreviation: Immunology Subsets: MEDLINE

Original Publication: Oxford : Blackwell Scientific Publications

Immunoconjugates*; Chemokine CCL5/*metabolism ; T-Lymphocytes/*immunology ; Tetradecanoylphorbol Acetate/*immunology; Abatacept ; Androstadienes/pharmacology ; Antigens, CD ; Antigens, Differentiation/immunology ; CD2 Antigens/immunology ; CD28 Antigens/immunology ; CD3 Complex/immunology ; CTLA-4 Antigen ; Calcium/metabolism ; Cell Culture Techniques ; Cell Division/immunology ; Down-Regulation/immunology ; Humans ; Phosphodiesterase Inhibitors/pharmacology ; Phosphoinositide-3 Kinase Inhibitors ; Tetradecanoylphorbol Acetate/antagonists & inhibitors ; Wortmannin

This study has examined the stimuli required for secretion of regulated upon activation, normal T-cell expressed, presumed secreted (RANTES) from T lymphocytes and found that stimuli such as phorbol 12-myristate 13-acetate (PMA), which are unable to support T-cell proliferation and interleukin-2 (IL-2) production, are nevertheless able to elicit strong secretion of RANTES. Conversely, stimuli such as CD2 and CD28 ligation, which are able to support T-cell proliferation, are unable to elicit RANTES secretion. Coligation of CD3 and CD28 drives T-cell proliferation to a similar degree as CD2 and CD28 coligation, yet also supports modest RANTES secretion. Furthermore, CD28 ligation enhances the secretion of RANTES stimulated by PMA and this costimulatory effect is abrogated by the phosphoinositide 3-kinase inhibitor wortmannin. Our data also indicate that the observed effects of PMA on RANTES secretion are probably due to activation of protein kinase C (PKC) isoenzymes, since RANTES secretion was unaffected by the non-PKC activating 4alpha-phorbol ester, whilst the general PKC inhibitor Ro-32-0432 inhibits PMA-stimulated RANTES secretion. Moreover, the effect of PMA appears to be chemokine-specific because PMA was unable to increase secretion of the related CC chemokine MIP-1alpha. Under stimulation conditions where increases in [Ca2+]i occur (e.g. PMA plus ionomycin or CD3 plus CD28 ligation) RANTES secretion can be severely reduced compared with the levels observed in response to the phorbol ester PMA. Hence, whilst PKC-dependent pathways are sufficient for strong RANTES secretion, a calcium-dependent factor is activated which negatively regulates RANTES secretion. This correlates well with the observation that ligation of cytolytic T lymphocyte-associated antigen-4 (CTLA-4) (expression of which has been reported to be dependent on a sustained calcium signal), inhibits RANTES secretion induced by CD3/CD28, but has no effect on PMA-stimulated RANTES secretion.

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0 (Androstadienes)
0 (Antigens, CD)
0 (Antigens, Differentiation)
0 (CD2 Antigens)
0 (CD28 Antigens)
0 (CD3 Complex)
0 (CTLA-4 Antigen)
0 (CTLA4 protein, human)
0 (Chemokine CCL5)
0 (Immunoconjugates)
0 (Phosphodiesterase Inhibitors)
0 (Phosphoinositide-3 Kinase Inhibitors)
7D0YB67S97 (Abatacept)
NI40JAQ945 (Tetradecanoylphorbol Acetate)
SY7Q814VUP (Calcium)
XVA4O219QW (Wortmannin)

Date Created: 20000930 Date Completed: 20001016 Latest Revision: 20191210

20240829

PMC2327056

10.1046/j.1365-2567.2000.00072.x

11012750