Making antigen invisible: a coinhibitory molecule regulates the interaction between T cells and dendritic cells.
Antigen-specific downregulation of T-cell effector function is critical for maintaining self-tolerance but it can promote pathogen persistence in chronic infections; consequently, the restoration of T-cell effector functions is a major goal of therapeutic vaccines against chronic viral infections and malignancies. Recently, a number of T-cell inhibitory receptors, most prominently programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4, have been described that are associated with T-cell exhaustion and tolerance. Blocking these receptors can restore T-cell function and, depending on the model, lead to autoimmune disease or successful viral elimination. Antibodies to PD-1 and cytotoxic T-lymphocyte antigen-4 are currently being tested in clinical trials in several malignant diseases and chronic hepatitis C as they are promising candidates for combination with both prophylactic and therapeutic vaccines. Given the central role of T-cell inhibitory receptors in the regulation of immune responses, understanding their molecular mode of action is of major importance. In the report from Fife and colleagues, two-photon laser scanning microscopy of mouse lymphoid and peripheral tissue has been employed to study the interaction of tolerized PD-1-expressing T cells with antigen-bearing dendritic cells in vivo. While tolerized T cells moved freely and did not make prolonged contacts with dendritic cells, addition of an antibody that blocked the interaction between PD-1 and its ligand PD-L1 lowered T-cell motility, enhanced T-cell-dendritic cell contacts and caused autoimmune disease in the nonobese diabetic mouse model of autoimmune diabetes. The authors conclude that PD-1-PD-L1 interactions mediate peripheral tolerance by inhibiting T-cell receptor-induced stop signals.
Diepolder
Helmut
H
Institute for Immunology and Medical Department II, Medical Faculty, Ludwig-Maximilians-University, Goethestr. 31, 80336 München, Germany. helmut.diepolder@med.uni-muenchen.de
Obst
Reinhard
R