Akt signaling is critical for memory CD8⁺ T-cell development and tumor immune surveillance.

Abstract

Memory CD8⁺ T cells confer long-term immunity against tumors, and anticancer vaccines therefore should maximize their generation. Multiple memory CD8⁺ T-cell subsets with distinct functional and homing characteristics exist, but the signaling pathways that regulate their development are ill defined. Here we examined the role of the serine/threonine kinase Akt in the generation of protective immunity by CD8⁺ T cells. Akt is known to be activated by the T-cell antigen receptor and the cytokine IL-2, but its role in T-cell immunity in vivo has not been explored. Using CD8⁺ T cells from <i>pdk1</i>^{<i>K465E/K465E</i>} knockin mice, we found that decreased Akt activity inhibited the survival of T cells during the effector-to-memory cell transition and abolished their differentiation into C-X-C chemokine receptor 3 (CXCR3)^loCD43^lo effector-like memory cells. Consequently, antitumor immunity by CD8⁺ T cells that display defective Akt signaling was substantially diminished during the memory phase. Reduced memory T-cell survival and altered memory cell differentiation were associated with up-regulation of the proapoptotic protein Bim and the T-box transcription factor eomesodermin, respectively. These findings suggest an important role for effector-like memory CD8⁺ T cells in tumor immune surveillance and identify Akt as a key signaling node in the development of protective memory CD8⁺ T-cell responses.