Distinct Cell Death Sensitivity and Adaptivity in T Cell Subsets Following Manipulation of the BCL-2 Family of Proteins

The BCL-2 family comprises an essential network of proteins that govern a cell's decision to live or die. An increasingly diverse number of BH3 mimetics have been developed to manipulate interactions between BCL-2 family proteins within diseased and normal cells. Based on lymphocyte dependency on these proteins for ontogeny and survival, we hypothesized that T cells would have unique differences in their BCL-2 repertoire at baseline and in response to BH3 mimetic treatment. Long-term targeting of BCL-2 proteins in T cell subsets and their ability to adapt to extensive BCL-2 family manipulation is largely unknown. We first used a genetic deletion model of Bim, a master BH3-only regulator of T cell survival, to evaluate long-term pressure. We demonstrate that BIM loss in T cells leads to upregulation of additional BH3-only proteins, including Puma, Noxa, and Bmf, with differential upregulation patterns in CD8+ versus CD4+ T cells. We then used the BCL-2 specific inhibitor ABT-199 to further assess differences in BCL-2 family regulation between CD8+ T cells, Tcons, and Tregs. We find that CD8+ T cells are more sensitive to BCL-2 inhibition than Tregs, likely due to a more BCL-2 dependent profile of CD8+ T cells. Tregs appear be more effective at adapting to BCL-2 targeting and rely on other anti-apoptotic proteins for survival, including MCL-1 and BCL-XL. This research provides new insight into the dynamic regulation and adaptivity of T cell subsets in response to genetic and small molecule targeting of the BCL-2 family proteins. This will contribute to an improvement in our ability to effectively use BH3 mimetics in the context of immune system modulation, which will lead to new therapeutic strategies for a myriad of diseases, including anti-cancer immune therapy, transplant tolerance, and autoimmunity.