Liver grafts from CD39-overexpressing rodents are protected from ischemia reperfusion injury due to reduced numbers of resident CD4+T cells

Recent data support a modulatory role for CD4 T cells in experimental renal ischemia-reperfusion injury (IRI). CD4 T cells can functionally differentiate to either a Th1 (IFN-γ producing) or the counterbalancing Th2 (IL-4) phenotype. The enzymes signal transducers and activators of transcription (STAT) 4 and STAT6 regulate Th1 or Th2 differentiation and cytokine production, respectively. We therefore hypothesized that mice that were STAT4 deficient would be protected from renal IRI and that STAT6-deficient mice would have a more severe course. Intracellular cytokine staining of splenocytes from STAT4–/– or STAT6–/– exhibited distinct IFN-γ and IL-4 cytokine expression profiles. STAT6–/– had markedly worse renal function and tubular injury postischemia compared with wild type. STAT4–/– had only mildly improved function. Renal phagocyte infiltration and ICAM-1 upregulation were similar in STAT4–/–, STAT6–/–, and wild type. To evaluate if the mechanism of the marked worsening in the STAT6–/– mice could be due to IL-4 deficiency, IL-4-deficient mice were studied and had similar postischemic phenotype to STAT6–/– mice. These data demonstrate that the STAT6 pathway has a major protective role in renal IRI. IL-4 deficiency is a likely mechanism underlying the STAT6 effect. A “yin-yang” role for inflammation is emerging in renal IRI, similar to recent observations in atherosclerosis.

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T cell–derived interleukin (IL)-21 promotes brain injury following stroke in mice

Journal of Experimental Medicine ◽

10.1084/jem.20131377 ◽

2014 ◽

Vol 211 (4) ◽

pp. 595-604 ◽

Cited By ~ 50

Author(s):

Benjamin D.S. Clarkson ◽

Changying Ling ◽

Yejie Shi ◽

Melissa G. Harris ◽

Aditya Rayasam ◽

...

Keyword(s):

T Cells ◽

Brain Injury ◽

T Cell ◽

Cerebral Ischemia ◽

Reperfusion Injury ◽

Cd4 T Cells ◽

Ischemia Reperfusion Injury ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Intracellular Cytokine Staining

T lymphocytes are key contributors to the acute phase of cerebral ischemia reperfusion injury, but the relevant T cell–derived mediators of tissue injury remain unknown. Using a mouse model of transient focal brain ischemia, we report that IL-21 is highly up-regulated in the injured mouse brain after cerebral ischemia. IL-21–deficient mice have smaller infarcts, improved neurological function, and reduced lymphocyte accumulation in the brain within 24 h of reperfusion. Intracellular cytokine staining and adoptive transfer experiments revealed that brain-infiltrating CD4+ T cells are the predominant IL-21 source. Mice treated with decoy IL-21 receptor Fc fusion protein are protected from reperfusion injury. In postmortem human brain tissue, IL-21 localized to perivascular CD4+ T cells in the area surrounding acute stroke lesions, suggesting that IL-21–mediated brain injury may be relevant to human stroke.

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