The human immune system recognizes neopeptides derived from mitochondrial DNA deletions

Area of Science:

• Immunology
• Molecular Biology
• Aging Research

Background:

• Accumulation of mitochondrial DNA (mtDNA) mutations with age generates neopeptides.
• Immune surveillance of these neopeptides may influence mt-related diseases and autoimmunity.
• Direct evidence for adaptive immune recognition of neo-mtpeptides was lacking.

Purpose of the Study:

• To investigate the immune system's recognition of neopeptides derived from mtDNA mutations.
• To determine if pre-existing T cells can respond to these neo-mtpeptides.
• To explore potential cross-reactivity with microbial or self-homologs.

Main Methods:

• Bioinformatic prediction of MHC binding for mtDNA-derived neopeptides.
• Experimental validation of MHC binding (HLA-A*02).
• Assessment of T cell responses (CD4+ and CD8+) from healthy donors.
• Analysis of cross-reactivity using microbial and self-homolog peptides.

Main Results:

• Six predicted neopeptides were confirmed to bind HLA-A*02.
• Human CD4+ and CD8+ T cells recognized and responded to these neopeptides.
• A promiscuous peptide (P9) was recognized by T cells from 75% of donors.
• Cross-reactivity was observed between T cells recognizing microbial/self-homologs and the neo-mtpeptide.

Conclusions:

• The immune system can recognize peptides arising from spontaneous somatic mtDNA mutations.
• Immune responses to neo-mtpeptides may be primed by foreign peptides (e.g., microbial).
• Cross-reactivity between T cells specific for foreign/self-homologs and altered mt peptides suggests a mechanism for autoimmunity.