Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection

By G. Oldenhove, N. Bouladoux, E. Wohlfert, J. Hall, David Chou, L. D. dos Santos, S. O’Brien, R. Blank, E. Lamb, Sundar Natarajan and 4 more. Immunity, 2009

634 citations recorded by the source corpus.

Using a model of lethal oral infection with Toxoplasma gondii, we examined the fate of both induced and natural regulatory T (Treg) cells in the face of strong inflammatory responses occurring in a tolerogenic-prone environment. We found that during highly T helper 1 (Th1) cell-polarized mucosal immune responses, Treg cell numbers collapsed via multiple pathways including blockade of Treg cell induction and disruption of endogenous Treg cell homeostasis. In particular, shutdown of interleukin 2 (IL-2) in the highly Th1 cell-polarized environment triggered by infection directly contributed to Treg cell incapacity to suppress effector responses and eventually leads to immunopathogenesis. Furthermore, we found that environmental cues provided by both local dendritic cells and effector T cells can induce the expression of T-bet transcription factor and IFN-γ by Treg cells. These data reveal a mechanism for Th1 cell pathogenicity that extends beyond their proinflammatory program to limit Treg cell survival.

Subfields: Epidemiology, Immunology, Parasitology

View Paper: https://www.semanticscholar.org/paper/706accaeadb5118d7e09338b05778a1440c9630c

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Citations in the corpus

Immunomodulatory functions of type I interferons (2012, background): “FOXP3 + T Reg cells show functional and phenotypical plasticity in response to environmental cues and are capable of secreting pro-inflammatory cytokines, for example during severe inflammatio”
Regulatory T Cells and Foxp3 (2011, background): “Provision of IL-2-anti-IL2 immune complexes rescued a loss of Treg cells (49).”
Interleukin-2 at the Crossroads of Effector Responses, Tolerance, and Immunotherapy (2013, positive): “gondii infection, there is a marked decrease in Treg cell numbers and function that was reversed by exogenous IL-2 (Oldenhove et al., 2009).”
Phenotypic and functional specialization of FOXP3+ regulatory T cells (2011, background): “Similarly, a recent study demonstrated that when IL-2 availability is limited during oral infection with Toxoplasma gondii , T Reg cells become IL-12 responsive, express high amounts of T-bet and acquire the ability to produce IFNγ, subsequently contributing to the fatal intestinal immunopathology”
Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses (2010, positive): “Consequently, Treg cells produce IFNg and potentially contribute to the tissue damage leading to death of the infected host (Oldenhove et al., 2009).”
Peripheral CD4 T cell differentiation regulated by networks of cytokines and transcription factors (2010, background): “Indeed, T-bet expression is upregulated in Tregs from mice infected with a lethal inoculum of Toxoplasma gondii; such Foxp3 cells produce IFNc (181).”
Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells (2012, background): “There is a debate about the stability of the T reg phenotype in general , and of Foxp3 expression in particular (Duarte et al., 2009; Oldenhove et al., 2009; Zhou et al., 2009; Rubtsov et al., 2010; Sharma et al., 2010; Bailey-Bucktrout and Bluestone, 2011).”