Protective role of IL-2 during activation of T cells with bryostatin 1

Pharmacologic agents such as bryostatin 1 (bryostatin) can regulate cell ac tivation, growth, and differentiation by modulating the activities of prote in kinase C isoenzymes. Inhibition of growth of tumor cells and activation of T lymphocytes in vitro are the most recognized consequences of bryostati n treatment. The effect of bryostatin on T cells ranges from induction of a poptotic cell death to T cell activation, expansion, and acquisition of ant igen-specific effector functions. Here, we describe the conditions under wh ich these wide ranging effects occur. Mouse mammary tumor 4TO7-IL-2-primed lymph node cells exposed ex vivo to bryostatin upregulated CD25 expression but lost the ability to secrete IL-2. Most of these cells died by apoptosis unless IL-2 was provided for the duration of bryostatin treatment. Analysi s of T cell repertoire by screening of T cells for the expression of differ ent V beta T cell receptor (TCR) families revealed that bryostatin-induced T cell death was unbiased and V beta-nonspecific, Within particular V beta clones, only CD25(+) T cells survived exposure to bryostatin and IL-2, Trea tment of 4TO7 tumor-bearing mice with a single injection of low dose bryost atin followed by multiple low doses of IL-2, but not with bryostatin alone, delayed tumor growth. These results indicate that activation of T cells wi th bryostatin should be carried out under protection of exogenous IL-2 to e nsure survival and expansion of T cells that may exhibit anti-tumor activit y. (C) 2000 International Society for Immunopharmacology. Published by Else vier Science Ltd, All rights reserved.