Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection

CXCR3 regulates stem and proliferative CD8+ T cells during chronic infection by promoting interactions with DCs in splenic bridging channels

“…Our transcriptional data revealed a drop in TGF-b signaling in parallel with an increase in mechanistic target of rapamycin (mTOR) activity at the T INT stage. This is in line with recent data from LCMV chronic infection showing that TGF-b signaling suppresses mTOR activity to preserve the quiescent stem-like memory population and that ablation of TGF-b signaling results in an increase in transitory intermediate cells (Gabriel et al, 2021). These observations imply that T cell migration out of the white pulp relieves the metabolic constrains imposed by TGF-b, allowing T cells to transition into a proliferative intermediate stage.…”

“…The localization of WT T MEM cells in the white pulp raises the following question: what aspects of the white pulp may support a stem-like fate? One defining feature of the white pulp niche is elevated TGF-b expression, which promotes memory fate during acute and chronic viral infection (Seo et al, 2016;Gabriel et al, 2021). Our transcriptional data revealed a drop in TGF-b signaling in parallel with an increase in mechanistic target of rapamycin (mTOR) activity at the T INT stage.…”

TGF-β1 potentiates Vγ9Vδ2 T cell adoptive immunotherapy of cancer

“…Finally, TGF-β has been shown to repress mammalian target of rapamycin (mTOR) signaling to promote a less exhausted T cell metabolic state. 42 We observed that γδ[T2] cells expressed gene sets that favored enhanced glucose generation, consumption, and fatty acid metabolism. Consequently, further metabolic characterization of these cells is warranted.…”

Mastering an exhausting marathon: how CD8+ T cells fine‐tune metabolic fitness

“…13 Moreover, it is well known that precursors irreversibly transition from a stem-like phenotype into cells that have a short or limited lifespan (Figure 1), but to date which metabolic pathways are linked to this transition has remained largely unknown. Here, the paper published by Gabriel et al 14 provides exciting new insight as the authors report a metabolic master "switch" that regulates the differentiation of T cells during chronic viral infections.…”

“…17 In chronic infection, rapamycin treatment caused a massive population shift towards the Id3 + Tim3 À precursor population: the transient inhibition of mTORC1 via rapamycin administered in an early time window (0-4 days) after chronic infection boosted the proliferation of exhausted T cells that produced high amounts of IFNc at later stages of the infection. 14 Interestingly, the authors revealed a possible therapeutic potential of targeting this pathway: this early treatment with rapamycin, combined with a late checkpoint inhibition via anti-PD-L1 blockade, results in further expansion of CX3CR1 + Tex cells with superior viral control. In response to this challenge, CD8 + T cells can acquire metabolically distinct differentiation stages.…”