Activation of Islet Autoreactive Naive T Cells in Infants Is Influenced by Homeostatic Mechanisms and Antigen-Presenting Capacity

摘要

Islet autoimmunity precedes type 1 diabetes onset. We previously found that islet autoimmunity rarely starts before 6 months of age but reaches its highest incidence already at ~1 year of age. We now examine whether homeostatic expansion and immune competence changes seen in a maturating immune system may account for this marked variation in islet autoimmunity risk in the first year of life. We found naive proinsulin- and GAD65-responsive T cells in cord blood (CB) of healthy newborns, with highest responses observed in children with type 1 diabetes-susceptible HLA-DRB1/DQB1 genotypes. Homeostatic expansion characteristics with increased IL-7 concentrations and enhanced T-cell responsiveness to IL-7 were observed throughout the first year of life. However, the ability of antigen-presenting cells to activate naive T cells was compromised at birth, and CB monocytes had low surface expression of CD40 and HLA classⅡ . In contrast, antigen presentation and expression of these molecules had reached competent adult levels by the high incidence age of 8 months. We propose that temporal changes in islet autoimmunity seroconversion in infants are a consequence of the changing balance between homeostatic drive and antigen presentation competence. These findings are relevant for early prevention of type 1 diabetes.