ADVANCED GLYCOSYLATION ENDPRODUCT-SPECIFIC RECEPTORS ON HUMAN AND RATT-LYMPHOCYTES MEDIATE SYNTHESIS OF INTERFERON-GAMMA - ROLE IN TISSUE REMODELING

During normal aging and in chronic diabetes the excessive accumulation of reactive glucose-protein or glucose-lipid adducts known as advance d glycosylation endproducts (AGEs) has been shown to induce tissue dys function, in part through interaction with AGE-specific receptors on m onocyte/macrophages and other cells. Recognizing that circulating lymp hocytes trafficking through tissues interact with tissue AGEs, we sear ched for the expression of AGE-binding sites on peripheral blood T lym phocytes. Resting rat and human T cells bound I-125-AGE-albumin with a n affinity of 7.8 x 10(7) M-1, whereas, after stimulation with phytohe magglutinin (PHA) for 48 h, binding affinity increased to 5.8 x 10(8) M-1. Flow cytometric analysis of resting rat T cells using polyclonal antibodies raised against rat liver AGE-binding proteins (p60 and p90) revealed the constitutive expression of both immunoreactivities. The number of resting CD4+ and CD8+ T cells positive for anti-p60 antibody binding (34.2 and 58.5%, respectively) increased to 92 and 90% of cel ls after 48-h stimulation with PHA. Exposure of PHA-activated T lympho cytes to AGE-albumin enhanced expression of interferon gamma (IFN-gamm a) mRNA 10-fold and induced greater elaboration of the mature protein than did exposure to unmodified protein or PHA treatment alone. These data indicate that T cells contain an inducible system of surface rece ptors for AGE-modified proteins, and that receptor occupancy is linked to lymphokine production. This T cell AGE-receptor system might serve to target lymphocytes to AGE-rich tissues and involve them in the reg ulation of tissue homeostasis either by assisting in macrophage-depend ent clearance of AGE-proteins, or by exerting direct antiproliferative action on mesenchymal cells. Under conditions of excessive AGE-protei n and AGE lipid accumulation (e.g., aging and diabetes), enhanced prod uction of AGE-induced IFN-gamma may accelerate immune responses that c ontribute to tissue injury.