Mcl-1 promotes survival of thymocytes by inhibition of Bak in a pathway separate from Bcl-2

The anti-apoptotic proteins Mcl-1 and Bcl-2 have been shown to be critical in T cell development and homeostasis, but the precise mechanism by which these proteins function in T cells and other cells of the body is unclear. Potential mechanisms have allowed both for overlapping and unique roles for these proteins due to their abilities to bind different pro-apoptotic Bcl-2 family members, but it is unclear which of these mechanisms are important in an in vivo context. By generation of various genetic mouse models, we have found that Mcl-1 deficient thymocytes die largely by a Bak-specific mechanism. In vivo deletion of Bak rescued the survival and developmental blocks of Mcl-1-deficient thymocytes at the double negative and single positive stages. Transgenic over-expression of Bcl-2 and in vivo deletion of Bax or Bim were unable to rescue Mcl-1-deficient thymocytes. Thus, Mcl-1 functions in a unique pathway from Bcl-2 in T lymphocytes, likely due to its specific ability to bind and sequester pro-apoptotic Bak. Together, these data provide an in vivo model for Mcl-1 activity and give us a greater understanding of the pathways that promote thymocyte survival.