PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis

• DOI: 10.1084/jem.20121416
• Publication Date: 2013-03-26T03:28:39Z
• Authors: Bernd H. Zinselmeyer; Sara Heydari; Catarina Sacristán; Debasis Nayak; Michael Cammer; Jasmin Herz; Xiaoxiao Cheng; Simon J. Davis; Michael L. Dustin; Dorian B. McGavern
• Keywords: CD4-Positive T-Lymphocytes; Mice, Knockout; Immunity, Cellular; Programmed Cell Death 1 Receptor; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; Viral Load; Antigens, Differentiation; Article; B7-H1 Antigen; 3. Good health; Interferon-gamma; Mice; 03 medical and health sciences; 0302 clinical medicine; Cell Movement; Animals; Lymphocytic choriomeningitis virus

Immune responses to persistent viral infections and cancer often fail because of intense regulation antigen-specific T cells—a process referred as immune exhaustion. The mechanisms that underlie the induction exhaustion are not completely understood. To gain novel insights into this process, we simultaneously examined dynamics virus-specific CD8+ CD4+ cells in living spleen by two-photon microscopy (TPM) during establishment an acute or infection. We demonstrate persistence maps anatomically splenic marginal zone/red pulp is defined prolonged motility paralysis cells. Unexpectedly, therapeutic blockade PD-1–PD-L1 restored cell within 30 min, despite presence high loads. This result was supported planar bilayer data showing PD-L1 localizes central supramolecular activation cluster, decreases antiviral motility, promotes stable immunological synapse formation. Restoration vivo followed recovery signaling effector functions, which gave rise a fatal disease mediated IFN-γ. conclude manifestation induced PD-1 prevents from performing their functions subjects them states negative regulation.