The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis
Open accessAbstract
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.
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Citations
Cites
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer
Brahmer, J. R., Tykodi, S. S., Chow, L. Q. M., Hwu, W.-J., Topalian, S. L., Hwu, P., Drake, C. G., Camacho, L. H., Kauh, J., Odunsi, K., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200694 · Cited by 7,945
PD-1 and Its Ligands in Tolerance and Immunity
Keir, M. E., Butte, M. J., Freeman, G. J., & Sharpe, A. H. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.26.021607.090331 · Cited by 5,378
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · cited 5×
“These mutations afford CL13 the ability to es tablish systemic persistence, which results in the engagement of immune dampening pathways such as the PD1 (Barber et al., 2006) and IL10 (Brooks et al., 2006b; Ejrnaes et al., 2006) that induce T cell exhaustion (Wherry, 2011).”
BackgroundInfluentialPD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
Day, C. L., Kaufmann, D. E., Kiepiela, P., Brown, J. A., Moodley, E. S., Reddy, S., Mackey, E. W., Miller, J. D., Leslie, A. J., DePierres, C., et al. (2006) · Nature · doi:10.1038/nature05115 · Cited by 2,680
Dong, H., Zhu, G., Tamada, K., & Chen, L. (1999) · Nature Medicine · doi:10.1038/70932 · Cited by 2,496
Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103
Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function
Zajac, A. J., Blattman, J. N., Murali-Krishna, K., Sourdive, D. J. D., Suresh, M., Altman, J. D., & Ahmed, R. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.12.2205 · Cited by 1,978
Yokosuka, T., Takamatsu, M., Kobayashi-Imanishi, W., Hashimoto-Tane, A., Azuma, M., & Saito, T. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20112741 · Cited by 1,161
Junt, T., Moseman, E. A., Iannacone, M., Massberg, S., Lang, P. A., Boes, M., Fink, K., Henrickson, S. E., Shayakhmetov, D. M., Di Paolo, N. C., et al. (2007) · Nature · doi:10.1038/nature06287 · Cited by 846
Cited by
Molecular and cellular insights into T cell exhaustion
Wherry, E. J., & Kurachi, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3862 · Cited by 4,652
T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition
Hui, E., Cheung, J., Zhu, J., Su, X., Taylor, M. J., Wallweber, H. A., Sasmal, D. K., Huang, J., Kim, J. M., Mellman, I., et al. (2017) · Science · doi:10.1126/science.aaf1292 · Cited by 1,689
“Current studies have suggested that PD-1 activation suppresses T cell receptor (TCR) signaling (21-23), CD28 costimulatory signaling (24), ICOS costimulatory signaling (25), or a combination of pathways.”
BackgroundCD8+ T cell differentiation and dysfunction in cancer
Philip, M., & Schietinger, A. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00574-3 · Cited by 1,052
Coinhibitory Pathways in Immunotherapy for Cancer
Baumeister, S. H., Freeman, G. J., Dranoff, G., & Sharpe, A. H. (2016) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112049 · Cited by 910
Dustin, M. L. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0161 · Cited by 502
Self-citation
Metadata
- Authors
- Zinselmeyer, B. H., Heydari, S., Sacristán, C., Nayak, D., Cammer, M., Herz, J., Cheng, X., Davis, S. J., Dustin, M. L., & McGavern, D. B.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2013-03-25
- Volume
- 210
- Issue
- 4
- Pages
- 757-774
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- OpenAlex
- W2141131774
- Cited by
- 258
- References
- 10
- FWCI
- 13.44
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Zinselmeyer, B. H., Heydari, S., Sacristán, C., Nayak, D., Cammer, M., Herz, J., Cheng, X., Davis, S. J., Dustin, M. L., & McGavern, D. B. (2013). PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20121416
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