Protective role of IL-2 during activation of T cells with bryostatin 1.
Pharmacologic agents such as bryostatin 1 (bryostatin) can regulate cell activation, growth, and differentiation by modulating the activities of protein kinase C isoenzymes. Inhibition of growth of tumor cells and activation of T lymphocytes in vitro are the most recognized consequences of bryostatin treatment. The effect of bryostatin on T cells ranges from induction of apoptotic cell death to T cell activation, expansion, and acquisition of antigen-specific effector functions. Here, we describe the conditions under which 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. Analysis of T cell repertoire by screening of T cells for the expression of different Vbeta T cell receptor (TCR) families revealed that bryostatin-induced T cell death was unbiased and Vbeta-nonspecific. Within particular Vbeta clones, only CD25(+) T cells survived exposure to bryostatin and IL-2. Treatment of 4TO7 tumor-bearing mice with a single injection of low dose bryostatin followed by multiple low doses of IL-2, but not with bryostatin alone, delayed tumor growth. These results indicate that activation of T cells with bryostatin should be carried out under protection of exogenous IL-2 to ensure survival and expansion of T cells that may exhibit anti-tumor activity.
Kos
F J
FJ
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA. fkos@hsc.vcu.edu
Cornell
D L
DL
Lipke
A B
AB
Graham
L J
LJ
Bear
H D
HD
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D054713:Bryostatins; D005260:Female; D007376:Interleukin-2 / Q000502:physiology*; D007783:Lactones / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D018942:Macrolides; D051379:Mice; D008807:Mice, Inbred BALB C; D011493:Protein Kinase C / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D054713:Bryostatins; D007376:Interleukin-2; D007783:Lactones; D018942:Macrolides; D015375:Receptors, Interleukin-2; C046785:bryostatin 1; D011493:Protein Kinase C