T cell differ­en­ti­a­tion and function are tightly regulated by numer­ous cellu­lar processes, includ­ing cellu­lar metab­o­lism, which can be signif­i­cantly affected by mitochon­dr­ial DNA (mtDNA) mutations. However, the impact of mtDNA mutational burden on T cell differ­en­ti­a­tion and functional hetero­gene­ity remains poorly under­stood. Thus, this project aims to charac­ter­ize the mtDNA mutational landscape and its functional conse­quences in human T cells using single-cell multi-omics approaches.

Naïve T cells undergo clonal expan­sion after encoun­ter­ing antigens and further differ­en­ti­ate into effec­tor cells. After the clear­ance of infected cells, a small propor­tion of T cells further differ­en­ti­ate into long-lived memory popula­tions. Recent advances in single-cell genomics have unrav­eled plastic­ity and functional hetero­gene­ity as well as novel subsets of human T cells. Moreover, studies have revealed the impor­tant role of mitochon­dr­ial function on T cell differ­en­ti­a­tion and function.

Mitochon­dria are known as the cell's power­house, carry­ing their own genomic DNA (mitochon­dr­ial DNA, mtDNA), which encodes 13 for proteins of the respi­ra­tory chain and their trans­la­tional machin­ery. Thus, mtDNA mutations can compro­mise cellu­lar metab­o­lism and function. Never­the­less, how mtDNA mutational burden and hetero­plasmy affect T cell differ­en­ti­a­tion and function remains unclear. Here, I hypoth­e­size that T cells will manifest cell fate and functional biases in response to the overall mutational burden of mtDNA mutations.

Recently, Dr. Leif Ludwig, the Hector Research Career Devel­op­ment Awardee 2020, devel­oped a novel multi-omics technique, known as DOGMA-seq, enabling the sequenc­ing of the mitochon­dr­ial genome, the assess­ment of chromatin acces­si­bil­ity, gene expres­sion, and protein profil­ing simul­ta­ne­ously in single cells. In this doctoral project, we will lever­age this technique to decipher the impact of the mitochon­dr­ial genome mutational landscape on T cell differ­en­ti­a­tion and function.