Pivotal role of cerebral interleukin-17–producing γδT cells in the delayed phase of ischemic brain injury

Abstract

Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that gammadeltaT lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gammadeltaT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gammadeltaT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

“…Moreover, there is good evidence that this protection of lymphocyte-deficient mice following stroke is due to the lack of T cells, and not B cells, as the reconstitution of B cells does not alter the protection observed in the Rag1 À/À mice. By contrast, when wild-type CD3 + T cells are transplanted back into Rag1 À/À or Rag2 À/À mice (also deficient in T and B lymphocytes), this protection is lost (Kleinschnitz et al, 2010b;Shichita et al, 2009;Yilmaz et al, 2006), confirming that T-cell-mediated damage occurs acutely after experimental stroke. Moreover, mice that lack RANTES (CCL5), a chemokine that recruits T cells (as well as other immune cells) into inflammatory sites (Appay and Rowland-Jones, 2001), have smaller infarct volumes than wild-type littermates.…”

“…One study even found improvements in functional outcome up to 15 days after cerebral ischemia (Wei et al, 2011). Shichita et al (2009) found FTY720 to inhibit T-cell infiltration into the infarcted zone, and others have reported fewer infiltrating neutrophils and activated microglia/macrophages in the ischemic lesion (Czech et al, 2009;Pfeilschifter et al, 2011b;Wei et al, 2011). Furthermore, FTY720 was found to reduce apoptotic cell death in the ischemic hemisphere (Czech et al, 2009;Hasegawa et al, 2010;Wei et al, 2011) as well as the expression of intercellular adhesion molecule-1-positive blood vessels in the brain (Wei et al, 2011).…”

Clinical Trials of Immunomodulation in Ischemic Stroke

“…Transgenic animals deficient in lymphocytes consistently have smaller infarcts in different stroke models [23][24][25][26]. Moreover, antibody-mediated depletion of CD4 + , CD8 + , and γδ T cells reduced infarct volume and improved functional outcome [25,[27][28][29]. The dynamics of this deleterious role of different proinflammatory T cells have not been fully elucidated.…”

The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability

“…The evidence suggests that there is minimal infiltration of peripheral cells in the healthy brain; this is probably primarily due to the fact that expression of chemotactic agents is low, because migration of cells appears to be controlled mainly by expression of chemokines and adhesion molecules and their receptors. However, there is a marked increase in cell infiltration following trauma (Shichita et al, 2009) and in neurodegenerative conditions (Stone et al, 2009;Togo et al, 2002) when the blood-brain barrier (BBB) is breached and when expression of chemotactic agents is increased.…”