T cells modulate the microglial response to brain ischemia

Abstract

Neuroinflammation after stroke is characterized by the activation of resident microglia and the invasion of circulating leukocytes into the brain. Although lymphocytes infiltrate the brain in small number, they have been consistently demonstrated to be the most potent leukocyte subpopulation contributing to secondary inflammatory brain injury. However, the exact mechanism of how this minimal number of lymphocytes can profoundly affect stroke outcome is still largely elusive. Here, using a mouse model for ischemic stroke, we demonstrated that early activation of microglia in response to stroke is differentially regulated by distinct T cell subpopulations – with TH1 cells inducing a type I INF signaling in microglia and regulatory T cells (TREG) cells promoting microglial genes associated with chemotaxis. Acute treatment with engineered T cells overexpressing IL-10 administered into the cisterna magna after stroke induces a switch of microglial gene expression to a profile associated with pro-regenerative functions. Whereas microglia polarization by T cell subsets did not affect the acute development of the infarct volume, these findings substantiate the role of T cells in stroke by polarizing the microglial phenotype. Targeting T cell-microglia interactions can have direct translational relevance for further development of immune-targeted therapies for stroke and other neuroinflammatory conditions.

Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

“…While this question remains to be definitively answered, microglial reactivation could serve to recruit T-cells 92 and microglial proximity to pericytes and endothelial cells suggest they could present MHC-I to infiltrating T-cells 93 . In turn, T-cells could modulate microglial phenotype 94 . In the APP/PSEN1 model used here, infiltration of T-cells has been reported 95 which means one possibility is that the induction of MHC-I observed here could be to signal to T-cells.…”

Sex and interferon gamma signaling regulate microglia migration in the adult mouse cortex in vivo

“…In the context of the present work, immune cells that secrete IFNγ such as T cells and monocytes, which are normally present in the meninges or recruited to sites of injury ( 69 , 70 ), could directly communicate with microglia to regulate mobility. Indeed, a fascinating study ( 71 ) showed that the recruitment of T cells after ischemic stroke, activated microglia in the peri-infarct region (i.e., deramified morphology) and induced gene expression associated with interferon signaling and chemotaxis.…”

Sex and interferon gamma signaling regulate microglia migration in adult mouse cortexin vivo

“…In the context of the present work, immune cells that secrete IFNγ such as T cells and monocytes, which are normally present in the meninges or recruited to sites of injury 65 , could directly communicate with microglia to regulate mobility. Indeed, a fascinating study by 66 showed that the recruitment of T cells after ischemic stroke, activated microglia in the peri-infarct region (i.e. de-ramified morphology) and induced gene expression associated with interferon signaling and chemotaxis.…”