Vannini, N. | bioRxiv Science

bioRxiv2023

Induction of mitophagy reverts age-associated decline of the hematopoietic and immune systems

Aging compromises hematopoietic and immune system functions, making elderly individuals especially susceptible to hematopoietic failure, infections and tumor development and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward myeloid lineage (myeloid-bias). These processes are accompanied by an aberrant accumulation of mitochondria in HSCs. The administration of the mitophagy-inducer Urolithin-A re-establishes the correct mitochondrial homeostasis in HSCs and completely restores the blood reconstitution capability of "old" HSCs. Moreover, Urolithin-A supplemented food restores lymphoid compartments, boosts HSCs function and improves the immune response to viral infection in old mice. Altogether our results demonstrate that targeting mitophagy reverts aging phenotype in the hematopoietic and immune system.

immunology↗

bioRxiv2022

TGFβ limits Myc-dependent TCR-induced metabolic reprogramming in CD8+ T cells

T cell activation is dependent upon the integration of antigenic, costimulatory and cytokine-derived signals and the availability and acquisition of nutrients from the environment. Furthermore, T cell activation is accompanied by reprogramming of cellular metabolism to provide the energy and building blocks for proliferation, differentiation and effector function. Transforming growth factor {beta} (TGF{beta}) has pleiotropic effects on T cell populations, having both an essential role in the maintenance of immune tolerance but also context-dependent pro-inflammatory functions. We set out to define the mechanisms underpinning the suppressive effects of TGF{beta} on mouse CD8+ T cell activation. RNA-sequencing analysis of TCR-stimulated T cells determined that Myc-regulated genes were highly enriched within gene sets downregulated by TGF{beta}. Functional analysis demonstrated that TGF{beta} impeded TCR-induced upregulation of amino acid transporter expression, amino acid uptake and protein synthesis. Furthermore, TCR-induced upregulation of Myc-dependent glycolytic metabolism was substantially inhibited by TGF{beta} treatment with minimal effects on mitochondrial respiration or mTOR activation. Thus, our data suggest that inhibition of Myc-dependent metabolic reprogramming represents a major mechanism underpinning the suppressive effects of TGF{beta} on CD8+ T cell activation.

immunology↗