Abstract
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.
Highlights
The immune system has to efficiently eliminate pathogens but simultaneously needs to avoid the potential self-damage and immunopathology caused by excessive immune activation
The molecular signature of exhausted T cells has been characterized in detail at the functional and transcriptional level, the immunological mechanisms that lead to T cell exhaustion during chronic infections remain poorly understood
Our present study reports two major findings that illustrate a pathway that contributes to T cell exhaustion during viral infection, and indicate its modulation by both, the pathogen and the host
Summary
The immune system has to efficiently eliminate pathogens but simultaneously needs to avoid the potential self-damage and immunopathology caused by excessive immune activation. Treg cells are best defined by expression of the signature transcription factor forkhead box P3, Foxp3 [2,3,4,5,6,7]. Their fundamental role in the maintenance of immune homeostasis and tolerance is well established [8,9,10] and unambiguously demonstrated by the severe multi-organ autoimmune disease, allergy and inflammatory bowel disease that develops in Foxp3-deficient mice or patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome [3,11,12,13]. The relevance of Treg cell responses for shaping adaptive immunity against pathogens, in particular in the context of chronic infections, refigmains much less understood
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