Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses.., 2021, Gabriel et al

[Andy]

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

Highlights

• Tpex cells preserve mitochondrial fitness during chronic infection
• TGF-β-mediated mTOR-inhibition preserves metabolism in Tpex cells
• TGF-β is a main driver of T cell exhaustion
• Early targeting of mTOR signaling promotes long-term T cell responses

Summary

Antigen-specific CD8+ T cells in chronic viral infections and tumors functionally deteriorate, a process known as exhaustion. Exhausted T cells are sustained by precursors of exhausted (Tpex) cells that self-renew while continuously generating exhausted effector (Tex) cells. However, it remains unknown how Tpex cells maintain their functionality. Here, we demonstrate that Tpex cells sustained mitochondrial fitness, including high spare respiratory capacity, while Tex cells deteriorated metabolically over time. Tpex cells showed early suppression of mTOR kinase signaling but retained the ability to activate this pathway in response to antigen receptor signals. Early transient mTOR inhibition improved long-term T cell responses and checkpoint inhibition. Transforming growth factor-β repressed mTOR signaling in exhausted T cells and was a critical determinant of Tpex cell metabolism and function. Overall, we demonstrate that the preservation of cellular metabolism allows Tpex cells to retain long-term functionality to sustain T cell responses during chronic infection.

Paywall, https://www.cell.com/immunity/fulltext/S1074-7613(21)00251-X

 

[SNT Gatchaman]

No longer pay-walled (PDF).

Some summary quotes —

CD8+ T cells responding to persistent antigenic stimulation as it occurs during chronic viral infections and cancer undergo a pro- cess known as T cell exhaustion, which is characterized by the impaired production of effector cytokines [...] While this deterioration of effector function limits productive immunity, it also constitutes a necessary adaptation of the immune system to prevent immune-mediated pathology.

The pool of exhausted CD8+ T cells is heterogenous and consists of subsets with distinct functional properties [...] Recent work has identified a population of exhausted cells that combines memory T cell characteristics with progenitor or precursor potential. These cells, which we refer to as precursors of exhausted T (Tpex) cells [...] possess long-term proliferative and self-renewal capacity and mediate the continuous replenishment of exhausted effector T (Tex) cells.

Recently, we and others have shown that Tpex cells develop early during infection and are the first to acquire features of exhaustion

Overall, from these results emerges a model according to which viral infection drives the differentiation of early precursor and effector cells from naive T cells. While the first wave of effector cells that differentiate in response to infection is fully functional but short-lived, precursor cells that develop in parallel can either differentiate into memory cells or, under conditions of ongoing infection, acquire features of exhaustion and differentiate into Tpex cells. Subsequently, Tpex cells sustain the effector response by continuously generating exhausted CX3CR1+ cells that retain some effector function and terminally exhausted CD101+ T cells, thus establishing the dynamics of a long-term T cell response.

Transforming growth factor-b (TGF-b) signaling is increased in T cells in chronic compared to acute infection and has been implicated in promoting viral persistence.

Upon TCR stimulation, multiple signaling pathways that lead to rapid proliferation and acquisition of effector function are triggered. This process is supported by a switch from catabolic to anabolic metabolism to support the energetic demands of effector cells. TCR-induced anabolic metabolism is, however, linked to the generation of short-lived effector cells, while long-term survival of memory cells requires the cessation of TCR signaling and the adoption of catabolic pathways, in particular, mitochondrial oxidative phosphorylation

Thus, tightly regulated cellular metabolism is a key determinant in the long-term survival of T cells.

Previous studies have shown that exhausted T cells are metabolically impaired, which would impede the long-term maintenance of antigen-specific T cells in response to chronic antigen. Thus, it is unclear how Tpex cells can sustain T cell responses to chronic viruses or tumors over long periods of time.

While early Tex cells displayed high activity of the mammalian target of rapamycin (mTOR), a central coordinator of anabolic metabolism, early Tpex cells exhibited high mitochondrial activity and spare respiratory capacity, but reduced mTOR activity. Throughout chronic infection, Tpex cells retained their metabolic characteristics and the ability to activate mTOR signaling in response to TCR signals, whereas Tex cells underwent metabolic exhaustion, including loss of mTOR signaling capacity. Mechanistically, TGF-b signaling reduced mTOR activity and promoted mitochondrial activity, thus priming long-term maintenance and function of Tpex cells.

Overall, we demonstrate that Tpex cells preserve their metabolism to retain long-term functionality, allowing them to sustain T cell responses during chronic infection, and identify the TGF-b-mTOR axis as critical in this process.

Concluding —

Antigen engagement drives an early dichotomy of effector and precursor T cells that is accompanied by the establishment of divergent metabolic profiles, which provide the foundation for the distinct functional and developmental properties of Tpex and Tex cells. While effector T cell metabolism runs unrestrained in ‘‘sprint’’ mode, early precursor T cells pace their bioenergetic requirements and thus prepare for the ‘‘marathon’’ required to sustain cytotoxic T cell responses long term. Critically, metabolic preservation of precursor T cells is accompanied by restrained effector function, a hallmark of exhaustion. Thus, exhaustion and long-term maintenance of T cell responses are intimately linked through TGF-b signaling and preserved cellular metabolism.