Rapamycin increases the yield and effector function of human γδ T cells stimulated in vitro

Clinical strategies to exploit V gamma 2V delta 2 T cell responses for immunotherapy are confronted with short-term increases in cell levels or activity and the development of anergy that reduces the response to therapy with succeeding treatments. We are exploring strategies to increase the yield and durability of elicited V gamma 2V delta 2 T cell responses. One approach focuses on the mammalian target of rapamycin (mTOR), which is important for regulating T cell metabolism and function. In V gamma 2V delta 2 T cells, mTOR phosphorylates the S6K1 and eIF4EBP1 signaling intermediates after antigen stimulation. Rapamycin inhibited these phosphorylation events without impacting Akt or Erk activation, even though specific inhibition of Akt or Erk in turn reduced the activation of mTOR. The effects of rapamycin on the T cell receptor signaling pathway lead to increased proliferation of treated and antigen-exposed V gamma 2V delta 2 cells. Rapamycin altered the phenotype of antigen-specific V gamma 2V delta 2 cells by inducing a population shift from CD62L + CD69- to CD62L-CD69+, higher expression of CD25 or Bcl-2, lower levels of CCR5 and increased resistance to Fas-mediated cellular apoptosis. These changes were consistent with rapamycin promoting cell activation while decreasing the susceptibility to cell death that might occur by CCR5 or Fas signaling. Rapamycin treatment during antigen-stimulation of V gamma 2V delta 2 T cells may be a strategy for overcoming current obstacles in tumor immunotherapy.