The TG2/LRP1 Pathway for T Cell Activation by Post-Translationally Modified Antigens.

Post-translational modifications (PTMs) can generate neo-epitopes, modified peptides that evade immune tolerance and trigger immune responses. This review focuses on the TG2/LRP1 pathway as a new paradigm for coupling the formation of post-translationally modified peptides with their effective presentation as T-cell antigens by dendritic cells. Transglutaminase 2 (TG2) catalyzes the Gln → Glu conversion of specific residues in peptides derived from dietary gluten thereby enhancing their affinity for HLA-DQ2, the principal genetic determinant of celiac disease. However, because such modified peptides are scarce in intestinal mucosa, an effective mechanism for lysosomal uptake by antigen-presenting cells (APCs) is necessary. Protein-protein interaction between certain peptide-bound TG2 complexes and the low-density lipoprotein receptor-related protein 1 (LRP1) results in efficient endocytosis of these antigenic peptides along with their concomitant release in the endo-lysosomal compartment as deamidated products. An analogous PTM-driven mechanism for antigen presentation may also operate in autoimmune conditions associated with peptidylarginine deiminase (PADI) activity, such as rheumatoid arthritis (RA). The exquisite cellular selectivity of the TG2/LRP1 pathway has implications not only for understanding its role in autoimmunity but also for its potential exploitation in vaccine design.