The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival
Open accessAbstract
Chronic infections induce T cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation. In fact, we noted that low-level antigen exposure promotes the formation of T cells with an acute phenotype in chronic infections. Unexpectedly, we found that T cell populations with an acute or chronic phenotype are maintained equally well in chronic infections and undergo comparable primary and secondary expansion. Thus, our observations contrast with the view that T cells with a typical chronic infection phenotype are severely functionally impaired and rapidly transition into a terminal stage of differentiation. Instead, our data unravel that T cells primarily undergo a form of phenotypic and functional differentiation in the early phase of a chronic LCMV infection without inheriting a net survival or expansion deficit, and we demonstrate that the acquired chronic phenotype transitions into the memory T cell compartment.
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Cites
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · cited 2×
“In all cases, we confirmed that T cells isolated from pure clone-13–infected mice exhibit the chronic phenotype.”
BackgroundResultPD-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
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
Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen
Doedens, A. L., Phan, A. T., Stradner, M. H., Fujimoto, J. K., Nguyen, J. V., Yang, E., Johnson, R. S., & Goldrath, A. W. (2013) · Nature Immunology · doi:10.1038/ni.2714 · Cited by 660 · cited 2×
“Such effector T cells would be advantageous in preventing immunopathology because the strong and aggressive immune responses found in an acute infection could be detrimental in persistently infected hosts (Cornberg et al., 2013; Doedens et al., 2013).”
BackgroundNakamoto, N., Cho, H., Shaked, A., Olthoff, K., Valiga, M. E., Kaminski, M., Gostick, E., Price, D. A., Freeman, G. J., Wherry, E. J., et al. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000313 · Cited by 380
Bengsch, B., Seigel, B., Ruhl, M., Timm, J., Kuntz, M., Blum, H. E., Pircher, H., & Thimme, R. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000947 · Cited by 373
Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation
Hertoghs, K. M. L., Moerland, P. D., van Stijn, A., Remmerswaal, E. B. M., Yong, S. L., van de Berg, P. J. E. J., van Ham, S. M., Baas, F., ten Berge, I. J. M., & van Lier, R. A. W. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42758 · Cited by 198
Cited by
Metabolic and epigenetic regulation of T-cell exhaustion
Franco, F., Jaccard, A., Romero, P., Yu, Y.-R., & Ho, P.-C. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00280-9 · Cited by 455
Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans
Galletti, G., De Simone, G., Mazza, E. M. C., Puccio, S., Mezzanotte, C., Bi, T. M., Davydov, A. N., Metsger, M., Scamardella, E., Alvisi, G., et al. (2020) · Nature Immunology · doi:10.1038/s41590-020-0791-5 · Cited by 299
Epigenetic regulation of T cell exhaustion
Belk, J. A., Daniel, B., & Satpathy, A. T. (2022) · Nature Immunology · doi:10.1038/s41590-022-01224-z · Cited by 319
Challenges in developing personalized neoantigen cancer vaccines
Katsikis, P. D., Ishii, K. J., & Schliehe, C. (2024) · Nature Reviews Immunology · doi:10.1038/s41577-023-00937-y · Cited by 258
Collier, J. L., Weiss, S. A., Pauken, K. E., Sen, D. R., & Sharpe, A. H. (2021) · Nature Immunology · doi:10.1038/s41590-021-00949-7 · Cited by 237
Metadata
- Authors
- Utzschneider, D. T., Alfei, F., Roelli, P., Barras, D., Chennupati, V., Darbre, S., Delorenzi, M., Pinschewer, D. D., & Zehn, D.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2016-07-25
- Volume
- 213
- Issue
- 9
- Pages
- 1819-1834
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- OpenAlex
- W2503575190
- Cited by
- 174
- References
- 8
- FWCI
- 7.23
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Utzschneider, D. T., Alfei, F., Roelli, P., Barras, D., Chennupati, V., Darbre, S., Delorenzi, M., Pinschewer, D. D., & Zehn, D. (2016). High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20150598
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