CONTROL OF CD4 EFFECTOR FATE - TRANSFORMING GROWTH-FACTOR-BETA-1 AND INTERLEUKIN-2 SYNERGIZE TO PREVENT APOPTOSIS AND PROMOTE EFFECTOR EXPANSION

The signals that determine the size and duration of the primary T cell immune response are not well defined. We studied CD4 T cells at an im portant checkpoint in their development: when they have become effecte rs and are ready to rapidly mediate effector functions, both via direc t interaction with antigen (Ag)-presenting cells and via cytokine prod uction. We determined the effects of specific Ag and the cytokines int erleukin (IL) 2 and transforming growth factor (TGF) beta 1 on T helpe r cell type 2 (Th2) effector apoptosis versus expansion. Th2-polarized effector cells were generated in vitro from naive CD4 T of T cell rec eptor transgenic mice, and then restimulated with or without peptide A g plus Ag-presenting cells and cytokines. In the absence of added cyto kines, effector cells cultured without Ag died of apoptosis after 4-7 d. Paradoxically, Ag both induced proliferation and high levels of cyt okine synthesis and accelerated effector cell death. IL-2 directly ind uced proliferation of effecters, supported and prolonged Ag-induced pr oliferation, and partially blocked apoptosis. TGF-beta did not effect proliferation or influence cytokine secretion, but it also partially b locked apoptosis. Together, IL-2 and TGF-beta synergized to almost com pletely block apoptosis, resulting in prolonged effector expansion and leading to the accumulation of a large pool of specific effecters. Wh en Ag and both cytokines were present, the effector population increas ed 10(4)-10(5)-fold over 20 d of culture. The synergy of IL-2 and TGF- beta suggests that they interfere with programmed cell death by distin ct mechanisms. Since Th2 effecters are specialized to help B cells dev elop into antibody-secreting plasma cells, these results suggest that the availability of Ag and of the cytokines IL-2 and TGF-beta is a key factor influencing the fate of Th2 effector cells and thus the size a nd duration of the primary antibody response.