PI3Kδ coordinates transcriptional, chromatin, and metabolic changes to promote effector CD8+ T cells at the expense of central memory

Abstract

Highlights d Activated PI3Kd drives accelerated effector T cell function and FasL-driven apoptosis d Activated PI3Kd increases IL-2, mTOR, and Myc signatures and alters metabolism d Activated PI3Kd is associated with decreased TCF1 and altered chromatin d After infection, PI3Kd drives terminal and long-lived effector cells but poor T CM

The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell Exhaustion

“…Conversely, recent work from our laboratory showed that expression of an activated PI3Kδ allele suppressed the maintenance of a TCF-1 + CD8 + T cell population and the development of central memory cells during acute viral infection. Instead, activated PI3Kδ-expressing CD8 + T cells were driven to a long-lived effector cell fate with increased expression of effector cytokines IFN-γ and TNF-α ( 8 ). Similarly, T cells from patients with the immunodeficiency, Activated PI3K Delta Syndrome, failed to maintain a TCF-1 + population when expanded in vitro ( 8 , 56 ).…”

“…Instead, activated PI3Kδ-expressing CD8 + T cells were driven to a long-lived effector cell fate with increased expression of effector cytokines IFN-γ and TNF-α ( 8 ). Similarly, T cells from patients with the immunodeficiency, Activated PI3K Delta Syndrome, failed to maintain a TCF-1 + population when expanded in vitro ( 8 , 56 ). Together these studies raise the possibility that inhibition of PI3Kδ could promote expansion of TCF-1 + pTex, thereby increasing the population that can respond to ICB ( Figure 2 ).…”

“…A specific subset of Tex cells, defined as ‘precursor exhausted’ or ‘stem-like’ progenitor (pTex) cells, retains some effector function and shares characteristics with memory cells ( Figure 1 ). pTex cells are defined by and require the expression of the transcription factor TCF-1, which is critical for T cell ‘stemness’ ( 5 – 7 ) and is essential for the development of central memory T cells during acute infection ( 7 , 8 ). TCF-1 + pTex cells both self-renew and, upon persistent antigen stimulation, convert into more ‘terminally exhausted’ states, as well as cytolytic effector-like cells ( 9 ).…”

Directing T-Cell Immune Responses for Cancer Vaccination and Immunotherapy

“…The PI3K delta subunit coordinates transcriptional, chromatin, and metabolic changes characterised by enhanced mTORC1 and c-Myc signatures to promote effector CD8 + T cells. This is associated increases in FAS-mediated apoptosis, reductions in transcription factors including TCF-1 and reductions in the generation of central memory [186]. The role of the PI3K delta subunit appears to have profound, differential effects CD8+ T-cells, controlling their fate, and represents a novel target for cancer immunotherapy.…”

“…Methods to inhibit mTOR include the inhibition of PI3K [186,199], which generates T-cells with a less differentiated state, or mTOR inhibition using rapamycin or its analogs (rapalogs), which enhance T-cell survival, increase mitochondrial respiration and support the generation of persistent memory T-cells [200]. This is hypothesized to be due to enhanced autophagy generating improved mitochondrial fitness [201,202].…”