Journal of Immunology Research

Review Article

Regulatory T Cell in Stroke: A New Paradigm for Immune Regulation

Table 1

Main findings of FoxP3⁺CD25⁺CD4⁺ Tregs in the pathogenesis of stroke.


Species	Model	Main findings	Authors

C57BL/6J mice	Transient MCAO (90 minutes)	Splenic atrophy; an increased percentage of FoxP3⁺CD4⁺ Tregs in blood and spleen	Offner et al. (2006) [89]

C57/BL6 mice	Transient MCAO (60 minutes)	Accumulation of FoxP3⁺ lymphocytes in the ischemic hemisphere; a high percentage of FoxP3⁺CD4⁺ and FoxP3⁺CD8⁺ lymphocytes in splenic T-lymphocytes	Gelderblom et al. (2009) [76]

C57BL/6 mice; Rag1^−/− mice; IL-10 knockout mice	Transient MCAO (30 minutes or 90 minutes)	Neuroprotective effects of FoxP3⁺CD25⁺CD4⁺ Tregs: inhibit inflammatory brain damage, restrain secondary infarct expansion, and attenuate functional neurological deficit; IL-10 signal pathway is essential for their immunomodulatory effect	Liesz et al. (2009) [12]

46 consecutive acute stroke patients	Clinical study	Increased apoptosis and a decline of FoxP3⁺CD25⁺CD4⁺ Tregs poststroke; decreased FoxP3⁺CD25⁺CD4⁺ Tregs did not show a correlation with the development of infection or stroke outcome	Urra et al. (2009) [78]

67 subjects (25 of them with acute ischemic stroke)	Clinical study	Increased number of CD25⁺CD4⁺ Tregs in the peripheral blood	Yan et al. (2009) [77]

CB-17 mice; SCID mice	Permanent MCAO	Deleption of CD25⁺ T cells suppressed generation of neural stem/progenitor cells and impaired functional recovery	Saino et al. (2010) [90]

C57BL/6 mice; 22 patients with acute ischemic stroke	Transient MCAO (90 minutes); an ex vivo analysis	The suppressive effect of Tregs in the mouse and humans is unaltered poststroke and reduced efficacy of circulating costimulatory cells after MCAO	Hug et al. (2011) [81]

FoxP3^DTR mice	Transient MCAO (60 minutes)	FoxP3⁺CD4⁺ Tregs depletion did not affect stroke infarct volume	Ren et al. (2011) [27]

700 subjects	Clinical study	No correlation between low levels of circulating FoxP3⁺CD25⁺CD4⁺ Tregs and an increased risk for the development of stroke	Wigren et al. (2012) [82]

Sprague-Dawley rats	Transient MCAO (120 minutes)	Adoptively transferred CD25⁺CD4⁺ Tregs ameliorated neuroinflammation, reduced brain infarct, and improved both short- and long-term neurological functions after cerebral ischemia; CD25⁺CD4⁺ Tregs reduce brain infarct size via BBB protection involving inhibition of neutrophil-derived MMP-9 production	Li et al. (2013) [64]

DEREG mice; C57BL/6 wild-type mice; Rag1^−/− mice	Transient MCAO (30 minutes or 60 minutes)	FoxP3⁺CD25⁺CD4⁺ Tregs strongly promoted acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature; established immunoregulatory effects of FoxP3⁺CD4⁺ Tregs had no functional relevance	Kleinschnitz et al. (2013) [28]

FoxP3^EGFP reporter mice; RAG1^−/− mice; C57BL/6J mice	Transient MCAO (30 minutes)	A strong accumulation and proliferation of FoxP3⁺CD25⁺CD4⁺ Tregs in the ischemic hemisphere in late phase (peaked around days 14 and up to days 30); delayed depletion of CD25⁺ Tregs does not worsen long-term outcome	Stubbe et al. (2013) [80]

MCAO: middle cerebral artery occlusion; MMP-9: Matrix metallopeptidase 9; BBB: blood-brain barrier; Tregs: regulatory T-cells.