Regulatory T lymphocytes as a therapy for ischemic stroke

Abstract

Unrestrained excessive inflammatory responses exacerbate ischemic brain injury and impede post-stroke brain recovery. CD4⁺CD25⁺Foxp3⁺ regulatory T (Treg) cells play important immunosuppressive roles to curtail inflammatory responses and regain immune homeostasis after stroke. Accumulating evidence confirms that Treg cells are neuroprotective at the acute stage after stroke and promote brain repair at the chronic phases. The beneficial effects of Treg cells are mediated by diverse mechanisms involving cell-cell interactions and soluble factor release. Multiple types of cells, including both immune cells and non-immune CNS cells, have been identified to be cellular targets of Treg cells. In this review, we summarize recent findings regarding the function of Treg cells in ischemic stroke and the underlying cellular and molecular mechanisms. The protective and reparative properties of Treg cells endorse them as good candidates for immune therapy. Strategies that boost the numbers and functions of Treg cells have been actively developing in the fields of transplantation and autoimmune diseases. We discuss the approaches for Treg cell expansion that have been tested in stroke models. The application of these approaches to stroke patients may bring new hope for stroke treatments.

Keywords: Brain repair; Immunoregulation; Neuroprotection; Regulatory T cell.

Figure 1.. Functions of regulatory T cells in an ischemic brain. Treg cells play diverse functions after ischemic stroke.

1) Protection: Upon ischemic injury, Treg cells are recruited toward the site of injury and protect CNS cells including neurons and oligodendrocytes. Treg cells also preserve blood–brain barrier integrity, which in turn inhibits the cerebral infiltration of peripheral inflammatory cells, such as effector T cells, dendritic cells, neutrophils, and macrophages. 2) Inflammation resolution: Treg cells participate in inflammation resolution by counteracting proinflammatory peripheral immune cells and proinflammatory microglia in the ischemic brain. Treg cells also inhibit toxic astrogliosis. 3) Regeneration: Treg cells promote recovery with ability to enhance neurogenesis, oligodendrocytes regeneration, and angiogenesis. 4) Neurovascular remodeling: Treg cells further enhance remyelination of axons and rewiring of neural circuitry. Consequently, Treg cells promote neurovascular remodeling after stroke.

Figure 2.. Mechanisms utilized by regulatory T cells to provide neuroprotection and enhance brain repair after ischemic stroke.

A. Treg cells restrain immune responses through 1) Soluble factors. Treg cells produce immunosuppressive factors, such as IL-10, TGF-β, and IL-35, thereby inhibiting effector T lymphocytes or other immune cells. 2) Cell contact-dependent mechanisms. For example, Treg cells relay inhibitory signals to neutrophils or effector T lymphocytes through PD-L1 and PD-1 interaction. The interaction of CTLA-4 on Treg cells with CD80/86 on dendritic cells down-regulate CD80/CD86 expression and thereby depriving co-stimulatory signal of effector T cells. Interaction between surface bound galectin-1 on Treg cells with its receptor on effector T cells can inhibit proliferation of effector T cells. 3) Treg cells inhibit IL-17⁺ γδ T cells in the small intestine and prevent the infiltration of IL-17⁺ γδ T cells into brain. B. Treg cells support tissue repair and regeneration through several different mechanisms. 4) Treg expressing PD-1 and OPN bind with the corresponding receptors on microglia to shift microglia towards a reparative phenotype. 5) Treg-derived soluble factors CCN3, IGF-1 and oncostatin M promote OPCs differentiation into new myelin-producing mature oligodendrocytes. 6) Treg cells act through AREG or IL-10 to inhibit neurotoxic astrocytic responses. 7) Treg cells promote brain regenerative processes by producing trophic factors such as IL-10 and BDNF.