Importance of T lymphocytes in brain injury, immunodeficiency, and recovery after cerebral ischemia

Abstract

Following an ischemic stroke, T lymphocytes become activated, infiltrate the brain, and appear to release cytokines and reactive oxygen species to contribute to early inflammation and brain injury. However, some subsets of T lymphocytes may be beneficial even in the early stages after a stroke, and recent evidence suggests that T lymphocytes can also contribute to the repair and regeneration of the brain at later stages. In the hours to days after stroke, T-lymphocyte numbers are then reduced in the blood and in secondary lymphoid organs as part of a 'stroke-induced immunodeficiency syndrome,' which is mediated by hyperactivity of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, resulting in increased risk of infectious complications. Whether or not poststroke T-lymphocyte activation occurs via an antigen-independent process, as opposed to a classical antigen-dependent process, is still controversial. Although considerable recent progress has been made, a better understanding of the roles of the different T-lymphocyte subpopulations and their temporal profile of damage versus repair will help to clarify whether T-lymphocyte targeting may be a viable poststroke therapy for clinical use.

Figure 1

Potential actions of T lymphocytes in the brain following stroke. Following cerebral ischemia and reperfusion, circulating T lymphocytes interact with neutrophils, macrophages, platelets, and endothelial cells (ECs), and may cross the blood–brain barrier (BBB) to infiltrate the injured tissue. The two broad subpopulations of mature circulating T lymphocytes are T-helper cells (i.e., CD4⁺) and cytotoxic T cells (i.e., CD8⁺). It appears that both subpopulations contribute significantly to acute poststroke brain injury via several mechanisms. The small subpopulation of CD4⁺ regulatory T cells (i.e., T_regs) may act to limit some of these damaging effects by other T cells. In addition, CD4⁺ T cells, perhaps especially T_regs, may contribute to later repair processes, such as neurogenesis, during brain recovery.