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

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    Author
    Utzschneider, DT; Alfei, F; Roelli, P; Barras, D; Chennupati, V; Darbre, S; Delorenzi, M; Pinschewer, DD; Zehn, D
    Date
    2016-08-22
    Source Title
    Journal of Experimental Medicine
    Publisher
    ROCKEFELLER UNIV PRESS
    University of Melbourne Author/s
    Utzschneider, Daniel
    Affiliation
    Microbiology and Immunology
    Metadata
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    Document Type
    Journal Article
    Citations
    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, 213 (9), pp.1819-1834. https://doi.org/10.1084/jem.20150598.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/255750
    DOI
    10.1084/jem.20150598
    Abstract
    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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