IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection

Schmitz, Iwana; Schneider, Christoph; Fröhlich, Anja; Frebel, Helge; Christ, Daniel; Leonard, Warren J.; Sparwasser, Tim; Oxenius, Annette; Freigang, Stefan Bernd; Kopf, Manfred (2013). IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection. PLoS pathogens, 9(5), e1003362. Public Library of Science 10.1371/journal.ppat.1003362

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Foxp3+ regulatory T (Treg) cells are essential for the maintenance of immune homeostasis and tolerance. During viral infections, Treg cells can limit the immunopathology resulting from excessive inflammation, yet potentially inhibit effective antiviral T cell responses and promote virus persistence. We report here that the fast-replicating LCMV strain Docile triggers a massive expansion of the Treg population that directly correlates with the size of the virus inoculum and its tendency to establish a chronic, persistent infection. This Treg cell proliferation was greatly enhanced in IL-21R-/- mice and depletion of Treg cells partially rescued defective CD8+ T cell cytokine responses and improved viral clearance in some but not all organs. Notably, IL-21 inhibited Treg cell expansion in a cell intrinsic manner. Moreover, experimental augmentation of Treg cells driven by injection of IL-2/anti-IL-2 immune complexes drastically impaired the functionality of the antiviral T cell response and impeded virus clearance. As a consequence, mice became highly susceptible to chronic infection following exposure to low virus doses. These findings reveal virus-driven Treg cell proliferation as potential evasion strategy that facilitates T cell exhaustion and virus persistence. Furthermore, they suggest that besides its primary function as a direct survival signal for antiviral CD8+ T cells during chronic infections, IL-21 may also indirectly promote CD8+ T cell poly-functionality by restricting the suppressive activity of infection-induced Treg cells.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology

UniBE Contributor:

Freigang, Stefan Bernd

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1553-7366

Publisher:

Public Library of Science

Language:

English

Submitter:

Andrea Arnold

Date Deposited:

07 Apr 2014 10:37

Last Modified:

30 Mar 2016 11:19

Publisher DOI:

10.1371/journal.ppat.1003362

PubMed ID:

23696736

BORIS DOI:

10.7892/boris.45895

URI:

https://boris.unibe.ch/id/eprint/45895

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