Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery

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Accumulating evidence implicates inflammation and immune responses in the pathophysiology of stroke. Immunomodulation has therefore emerged as a promising therapy for stroke. Regulatory lymphocytes, including CD4+CD25+ regulatory T cells (CD4+ Treg) and IL-10+ regulatory B cells (Bregs) are established modulators of immune responses in the injured brain. We recently discovered that another specialized T cell subpopulation—the CD8+CD122+CD49dhigh regulatory T cell—is among the first to enter the ischemic brain, even preceding the infiltration of CD4+ Tregs and Bregs. The primary function of CD8+ Tregs is to modulate the activities of other immune cells, especially effector T lymphocytes, and to maintain immune homeostasis. We found that selective depletion of circulating CD8+ Tregs exacerbated brain injury and functional outcomes at 3 and 7 days after stroke, and this could be reversed by the reconstitution of CD8+ Tregs. These exciting results suggest that CD8+ Tregs are natural defenders against ischemic brain injury. Further pilot studies discovered that: 1) CD8+ Treg-afforded early protection relies on their infiltration into the ischemic brain, as CD8+ Tregs lacking the “brain targeting signal” CXCR3 do not infiltrate into the ischemic brain and lose their capacity to reduce brain infarction in CD8+ Treg-depleted mice. 2) The infiltrated CD8+ Tregs undergo genomic reprogramming upon brain infiltration and transcriptional upregulation of a group of genes that possess inflammation-resolving and/or neurorestorative functions, including the leukemia inhibitory factor (LIF) receptor and epidermal growth factor-like transforming growth factor (ETGF). 3) Post-stroke adoptive transfer of CD8+ Tregs significantly reduces brain infarct, enhances white matter integrity, and improves neurological functions up to 14d after tMCAO. 4) Adoptive transfer of ETGF-deficient CD8+ Treg fails to protect against tMCAO. The current proposal will further explore the effects of CD8+ Tregs in ischemic stroke and develop CD8+ Treg adoptive transfer as an immune therapeutic therapy for stroke. The novel central hypothesis to be tested is that brain infiltration of CD8+ Tregs promotes long-term neurological recovery after stroke through LIF/LIFR/ETGF-mediated neuroprotection, resolution of neuroinflammation, and neurorestorative mechanisms. Three specific aims are proposed. Aim 1. Establish post-stroke adoptive transfer of CD8+ Tregs as a clinically relevant treatment against acute ischemic brain infarct. Aim 2. Test the hypothesis that post-stroke adoptive transfer of CD8+ Tregs promotes long-term neurological recovery and neurorestoration after ischemic stroke. Aim 3. Test the hypothesis that LIF/LIFR-mediated release of ETGF is essential for CD8+ Treg-afforded neuroprotection and neurorestoration. This study will be the first to rigorously investigate the role of CD8+ Tregs in ischemic brain injury. The results will improve our understanding of stroke immunomodulation and shed light on CD8+ Treg transfer as a potential therapeutic strategy.