PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis
Zinselmeyer BH, Heydari S, Sacristán C, Nayak D, Cammer M, Herz J, Cheng X, Davis SJ, Dustin ML, McGavern DB. (2013), J Exp Med. 210, 757-74
Immune responses to persistent viral infections and cancer often fail because of intense regulation of antigen-specific T cells – a process referred to as immune exhaustion. The mechanisms that underlie the induction of exhaustion are not completely understood. To gain novel insights into this process, we simultaneously examined the dynamics of virus-specific CD8+ and CD4+ T cells in the living spleen by two-photon microscopy (TPM) during the establishment of an acute or persistent viral infection. We demonstrate that immune exhaustion during viral persistence maps anatomically to the splenic marginal zone/red pulp and is defined by prolonged motility paralysis of virus-specific CD8+ and CD4+ T cells. Unexpectedly, therapeutic blockade of PD-1–PD-L1 restored CD8+ T cell motility within 30 min, despite the presence of high viral loads. This result was supported by planar bilayer data showing that PD-L1 localizes to the central supramolecular activation cluster, decreases antiviral CD8+ T cell motility, and promotes stable immunological synapse formation. Restoration of T cell motility in vivo was followed by recovery of cell signaling and effector functions, which gave rise to a fatal disease mediated by IFN-γ. We conclude that motility paralysis is a manifestation of immune exhaustion induced by PD-1 that prevents antiviral CD8+T cells from performing their effector functions and subjects them to prolonged states of negative immune regulation.
Key figure: Antiviral T cell dynamics after acute versus persistent infection
(A) TPM was used to examine the dynamics of CD8+ P14 (red) and CD4+ SMARTA (green) T cells in the spleen after an acute (Arm) or a persistent (CL13) infection (n = 5 mice). Representative 3D reconstructions of two-photon z stacks are shown for infected mice at day 7 after infection (left). The dashed white lines demarcate the border between the splenic red (RP) and white pulp (WP). The white boxes represent regions of interest from the white or red pulp magnified in the panels on the right. The magnified views show antiviral T cell movement over a 5-min time interval. Blue tracks follow the movement of P14 cells, whereas magenta tracks follow SMARTA cells. Note that nearly all highlighted T cells move over the denoted time interval except for P14 and SMARTA cells residing in the red pulp of CL13-infected mice (yellow arrowheads). Bars: (left) 100 µm; (right) 40 µm. See Videos 1–3. (B and C) Mean track velocities (µm/min) of CD8+ P14 (red) and CD4+ SMARTA (green) cells were quantified in the splenic red and white pulp at days 4 (B) and 7 (C) after Arm or CL13 infection (n = 5 mice). Asterisks denote statistically significant differences (P < 0.05). Each dot represents the track of an individual T cell. Horizontal black bars denote the mean of each group. Data are representative of five independent experiments.