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

Abstract

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.