Supplementum 270: Abstracts of the Annual congress of the Swiss Society for Allergology and Immunology

Aims: Impaired mitophagy leads to dysfunctional mitochondria accumulation and tumor-infiltrating T lymphocytes (TILs) exhaustion.However, the mechanisms connecting the accumulation of dysfunctional mitochondria and T cell exhaustion remain poorly understood.We speculate that cells employ alternative strategies to remove depolarized mitochondria, potentially inducing CD8 + T cell exhaustion.Methods: 1) a degron-mCherry reporter and a regulatory heme (RH) detection assay were developed to examine protein degradation.2) the correlation between RH and CD8 + T cell differentiation was investigated by detecting RH concentration and BACH2 and BLIMP1 expression in exhausted CD8 + T cells.3) hemin, a heme mimic, was used to assess the effect on CD8 + T cell exhaustion.4) the heme-binding site mutated BACH2 was utilized to explore the mechanism of heme-induced exhaustion.5) PGRMC2, responsible for heme import into the nucleus, was knocked out to verify the impact on TILs' exhaustion.Results: CD8 + T cells with dysfunctional mitochondria engage mitochondrial protein degradation, leading to increased RH concentration.RH correlates with TILs differentiation, and exogenous heme directly induces the BACH2-BLIMP1 transcriptional networks, which is essential for commitment of T cell exhaustion.Targeting PGRMC2 to reduce RH nuclear distribution ameliorates CD8 + T cell exhaustion and enhancing mitochondrial fitness.Conclusions: Heme-mediated reprogramming guides CD8 + T cell exhaustion in response to mitochondrial dysfunction.Manipulating heme signaling can be exploited to restore mitochondrial fitness and tailor T cell-based cellular therapies.