Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis

We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2(−/−) mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim(+/−)Bcl-2(−/−) mice, but were largely restored in Bim(−/−)Bcl-2(−/−) mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim(−/−), T cells. Further, T cells from Bim(+/−)Bcl-2(−/−) mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8(+) T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4(+) T cells did not. In contrast, Bim(+/−)Bcl-2(−/−) mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim(+/−)Bcl-2(−/−) mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells.