Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism

Mauro Corrado,Dijana Samardžić,Luca Scorrano,Marta Giacomello,Nisha Rana,Erika L Pearce

doi:10.1038/s41418-021-00747-6

Abstract

Optic atrophy 1 (OPA1), a mitochondria-shaping protein controlling cristae biogenesis and respiration, is required for memory T cell function, but whether it affects intrathymic T cell development is unknown. Here we show that OPA1 is necessary for thymocyte maturation at the double negative (DN)3 stage when rearrangement of the T cell receptor β (Tcrβ) locus occurs. By profiling mitochondrial function at different stages of thymocyte maturation, we find that DN3 cells rely on oxidative phosphorylation. Consistently, Opa1 deletion during early T cell development impairs respiration of DN3 cells and reduces their number. Opa1-deficient DN3 cells indeed display stronger TCR signaling and are more prone to cell death. The surviving Opa1−/− thymocytes that reach the periphery as mature T cells display an effector memory phenotype even in the absence of antigenic stimulation but are unable to generate metabolically fit long-term memory T cells. Thus, mitochondrial defects early during T cell development affect mature T cell function.

Highlights

The T cell repertoire develops from precursor cells migrating from the bone marrow into the thymus where a complex multistep maturation program generates functional CD4+ and CD8+ T cells able to discriminate self/non-selfantigen [1, 2]
Seahorse analyses of oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) to follow mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis indicated that bulk thymocytes were largely oxidative, with high spare respiratory capacity (SRC) after mitochondrial uncoupling with fluoro-carbonyl cyanide phenylhydrazone (FCCP) (Fig. 1D–F)
When we increased the granularity of our analysis, we found that both basal and maximal OCR and ECAR were higher in DN3 compared to DN4 cells (Fig. 1H, I)

Summary

Introduction

The T cell repertoire develops from precursor cells migrating from the bone marrow into the thymus where a complex multistep maturation program generates functional CD4+ and CD8+ T cells able to discriminate self/non-selfantigen [1, 2].

Methods

Results

Conclusion