High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival

Utzschneider, D. T. and Alfei, F. and Roelli, P. and Barras, D. and Chennupati, V. and Darbre, S. and Delorenzi, M. and Pinschewer, D. D. and 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, 213 (9). pp. 1819-1834.

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Medical Microbiology > Experimental Virology (Pinschewer)
UniBasel Contributors:Pinschewer, Daniel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Rockefeller University Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Jan 2019 13:21
Deposited On:06 Jan 2019 13:21

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