T-CELL RESCUE OF MONOCYTES FROM APOPTOSIS - ROLE OF THE CD40-CD40L INTERACTION AND REQUIREMENT FOR CD40-MEDIATED INDUCTION OF PROTEIN-TYROSINE KINASE-ACTIVITY

Circulating monocytes have a limited life span and will undergo apopto sis in the absence of specific stimuli, Recent studies have demonstrat ed that monocytes can be rescued from apoptosis via lipopolysaccharide (LPS) activation or stimulation with interleukin-l or tumor necrosis factor-alpha. Based on previous studies from our laboratory, we hypoth esized that, in nonseptic (e.g., autoimmune) inflammation, the presenc e of activated T cells may enhance monocyte longevity through T cell c ontact-dependent signaling. Plasma membranes prepared from 6 h activat ed (Tm-A) and resting (Tm-R) purified CD4(+) T cells were added to res ting elutriation-purified monocytes cultured in serum-free medium, Cel ls were assayed for degree of apoptosis occurring over a 72-h incubati on using both agarose gel electrophoresis and flow cytometry, The addi tion of Tm-A (but not Tm-R) was capable of blocking monocyte apoptosis and the ability of Tm-A to rescue monocytes was abrogated by the addi tion of anti-CD40L antibodies, Rescue of monocytes from apoptosis coul d also be mediated by direct cross-linking of monocyte CD40. Inhibitor s of tyrosine kinase activity blocked both Tm-A and anti-CD40-mediated rescue of monocytes from apoptosis, suggesting a primary role of a ty rosine kinase signaling pathway in the events controlling monocyte lon gevity.