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 pdk1K465E/K465E 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)loCD43lo 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.

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

“…This has already been described for hematopoietic stem cells which, as compared to mature blood cells, rely more on glycolysis than on oxidative phosphorylation. 42,43 As hematopoietic stem cells reside in stem cell niches with low oxygen levels, they are highly dependent on anaerobic metabolism. Interestingly, low oxygen levels stabilize and activate HIF, 44 which is important for the maintenance of hematopoietic stem cells and promotes self-renewal of embryonic stem cells.…”

The role of cytokines in T‐cell memory in health and disease

“…Further evidence supporting the importance of T cells and especially memory T cells comes from different mouse models. IL‐2‐, IL‐7‐, or IL‐15‐mediated proliferation and activation of adoptively transferred antigen‐specific CD4 + or CD8 + T cells cured established large tumors . This concept was tested in clinical trials using lymphodepletion before adoptive transfer of in vitro cultured tumor antigen‐specific T cells, inducing potent anti‐tumor responses .…”

Lack of Sprouty 1 and 2 enhances survival of effector CD8 + T cells and yields more protective memory cells

“…To address how DKO CD8 + T cells form more memory cells, we reasoned that Spry1/2 may regulate the activity of the metabolic checkpoint kinase, mechanistic target of rapamycin (mTOR), which is essential for sustaining the activation and survival of effector and memory CD8 + T cells. mTOR coordinates effector and memory CD8 + T cell generation in part by controlling both metabolic and transcriptional reprogramming through the mTORC1-mTORC2-AKT-FoxO1 signaling axis, which controls the downstream master transcription factors T-bet, Eomesodermin (Eomes), and Tcf-1 (14,16,(50)(51)(52)(53). These transcription factors, in turn, are critical in orchestrating the development of memory CD8 + T cells (14,43,(54)(55)(56).…”

“…The mTORC1-mTORC2-Akt-FoxO1 signaling axis plays a critical role in CD8 + T cell memory development via specific transcriptional reprogramming (14,16,(50)(51)(52)(53). Nuclear FoxO1 directly regulates the expression of T-bet and Eomes, and loss of FoxO1 impairs memory development and recall responses (13,14,50,51).…”