TPP2 (tripeptidyl peptidase 2) is a cytosolic exopeptidase that cleaves N-terminal tripeptides from polypeptides, functioning as a component of the proteolytic cascade downstream of the 26S proteasome 1. It plays a crucial role in intracellular amino acid homeostasis 1 and maintains calcium and phospholipid homeostasis in the central nervous system 2. Mechanistically, TPP2 operates through a 'molecular ruler mechanism' to remove tripeptides from free amino termini 3. Beyond proteasomal protein degradation, TPP2 is involved in HLA/antigen complex processing 4 and influences cell survival, with overexpression promoting cell growth and apoptosis resistance, while inhibition increases apoptotic sensitivity 3. Clinically, TPP2 deficiency manifests as Immunodeficiency 78 with autoimmunity and developmental delay 5. Biallelic TPP2 variants cause severe immune dysregulation (immunodeficiency with autoimmunity), intellectual disability, and autoimmune cytopenias 4. Additionally, certain TPP2 missense mutations are associated with sterile brain inflammation mimicking multiple sclerosis 6. TPP2 deficiency requires urgent clinical recognition for immune surveillance and potential hematopoietic stem cell transplantation consideration 4.