Breakdown of T cell tolerance and autoimmunity in primary immunodeficiency—lessons learned from monogenic disorders in mice and men

A key feature of the immune system is the capacity to monitor and control infections from non-self pathogens while maintaining tolerance to self-antigens. Primary immunodeficiencies (PID) are characterized by an increased susceptibility to infections, often associated with aberrant inflammatory responses and a concomitant high prevalence of autoimmunity. Autoimmunity in PID raises a conundrum: How can an immune system fail to respond to non-self pathogens while reacting vigorously to self-antigens? Recent advances from studies of PID patients and related animal models have revealed the crucial role of Aire-induced expression of self-antigens for deletion of autoreactive T cells in the thymus (central tolerance). Moreover, lessons from PID have provided unequivocal evidence for the essential role of regulatory T cells in suppressing autoreactive T cells in the periphery. Finally, findings from PID have broadened our understanding of how homeostatic proliferation and increased load or decreased clearance of apoptotic cells and non-self pathogens can lead to breakdown of peripheral tolerance.