IMMUNOPA-8T · Deciphering OPA1 regulation and function in human CD8⁺ T cells across scales

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Project objective

CD8⁺ T cells are central to adaptive immunity, eradicating pathogens and tumours while sustaining immune homeostasis. Their fate is shaped not only by transcriptional and signalling programmes but also by organellar organisation, an emerging regulatory layer. The mitochondrial GTPase Optic Atrophy 1 (OPA1) is uniquely positioned within this layer. By controlling inner membrane fusion and the assembly of cristae junctions, it tunes mitochondrial function. OPA1 is regulated through alternative splicing and proteolytic cleavage, generating isoforms whose balance dictates mitochondrial and cellular outcomes. Mutations disrupting this balance underlie cellular and systemic dysfunction, including immunopathologies. Existing immunological knowledge derives almost exclusively from murine knockout models, which lack isoform diversity and the nuanced regulation of the human system. IMMUNOPA-8T addresses this critical gap through three integrated aims that together define how OPA1 regulation shapes human CD8⁺ T cell biology in health and disease.Aim 1 will deliver the first molecular and ultrastructural atlas of OPA1 across human T cell proliferative trajectories, by integrating proteogenomic approaches with volumetric electron microscopy.Aim 2 will establish a genetic manipulation platform to mechanistically dissect isoform- and cleavage-specific OPA1 functions, combining precise editing with functional, metabolic, and ultrastructural phenotyping.Aim 3 will translate these insights into a disease context, profiling OPA1 status in post-transplant lymphoproliferative disease (PTLD) and applying mechanistic discoveries to engineer ultrastructurally optimised CAR-T cells targeting EBV-driven lymphoma.By linking molecular regulation, ultrastructural organisation, and function, IMMUNOPA-8T aims to open a new dimension of human T cell biology and unlock novel avenues for therapeutic innovation.

Original text from CORDIS.

Participants

• UNIVERSITAT BASEL · BaselCoordinatorSwitzerland

Links

• View on CORDIS
• DOI: 10.3030/101284915