Abstract
CD4 + T cells provide a neuro-immunological link in the regulation of adult hippocampal neurogenesis, but the exact mechanisms underlying enhanced neural precursor cell proliferation and the relative contribution of different T helper (Th) cell subsets have remained unclear. Here, we explored the pro-proliferative potential of interleukin 17-producing T helper (Th17) cells, a developmentally and functionally distinct Th cell subset that is a key mediator of autoimmune neurodegeneration. We found that base-line proliferation of hippocampal precursor cells in a T cell-deficient mouse model of impaired hippocampal neurogenesis can be restored upon adoptive transfer with homogeneous Th17 populations enriched for myelin-reactive T cell receptors (TCR). In these experiments, enhanced proliferation was independent of direct interactions of infiltrating Th17 cells with precursor cells or neighboring cells in the hippocampal neurogenic niche. Complementary studies in immunocompetent mice identified several receptors for Th17 cell-derived cytokines with mRNA expression in hippocampal precursor cells and dentate gyrus tissue, suggesting that Th17 cell activity in peripheral lymphoid tissues might promote hippocampal neurogenesis through secreted cytokines.
Highlights
In the hippocampus of the adult brain, neurogenesis originates from neural precursor cells residing in the subgranular zone of the dentate gyrus that proliferate and differentiate in response to intrinsic and extrinsic stimuli, allowing adaptation of the neuronal network to changing needs throughout life[1,2]
We found that base-line proliferation of hippocampal precursor cells in a T cell-deficient mouse model of impaired hippocampal neurogenesis can be restored upon adoptive transfer with homogeneous Th17 populations enriched for myelin-reactive T cell receptors (TCR)
Previous studies on mice with transgenic expression of a myelinspecific TCR on CD4+ T cells[5] and a non-TCR transgenic mouse model of MOG-inducible EAE9 have provided the first evidence that encephalitogenic CD4+ T cell activity can promote hippocampal precursor cell proliferation and adult neurogenesis
Summary
In the hippocampus of the adult brain, neurogenesis originates from neural precursor cells residing in the subgranular zone of the dentate gyrus that proliferate and differentiate in response to intrinsic and extrinsic stimuli, allowing adaptation of the neuronal network to changing needs throughout life[1,2]. Besides innate immune mechanisms[3,4], CD4+ T cells of the adaptive immune system promote adult hippocampal neurogenesis and convey functional benefits in reversal learning that have been related to adult neurogenesis[5,6,7]. The relative contribution of the activation or differentiation status of the CD4+ T cells to their proneurogenic activity remains to be determined. This includes CD4+ T cell-derived soluble factors that could either act directly on hippocampal precursor cells or promote precursor cell activity through indirect mechanisms, e.g. by acting on neighbouring cells within the neurogenic niche of the adult hippocampus
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