Meningeal γδ T cells are biased toward IL-17 production and control hippocampal synaptic plasticity and short-term memory.

Neuroinflammation in patients with Alzheimer's disease (AD) and related mouse models has been recognized for decades, but the contribution of the recently described meningeal immune population to AD pathogenesis remains to be addressed. Here, using the 3xTg-AD model, we report an accumulation of interleukin-17 (IL-17)-producing cells, mostly γδ T cells, in the brain and the meninges of female, but not male, mice, concomitant with the onset of cognitive decline. Critically, IL-17 neutralization into the ventricles is sufficient to prevent short-term memory and synaptic plasticity deficits at early stages of disease. These effects precede blood-brain barrier disruption and amyloid-beta or tau pathology, implying an early involvement of IL-17 in AD pathology. When IL-17 is neutralized at later stages of disease, the onset of short-memory deficits and amyloidosis-related splenomegaly is delayed. Altogether, our data support the idea that cognition relies on a finely regulated balance of "inflammatory" cytokines derived from the meningeal immune system.

CD4⁺Foxp3⁺ regulatory T cells (T_reg cells) are largely autoreactive yet escape clonal deletion in the thymus. We demonstrate here that CD27–CD70 co-stimulation in the thymus rescues developing T_reg cells from apoptosis and thereby promotes T_reg cell generation. Genetic ablation of CD27 or its ligand CD70 reduced T_reg cell numbers in the thymus and peripheral lymphoid organs, whereas it did not alter conventional CD4⁺Foxp3⁻ T cell numbers. The CD27–CD70 pathway was not required for pre-T_reg cell generation, Foxp3 induction, or mature T_reg cell function. Rather, CD27 signaling enhanced positive selection of T_reg cells within the thymus in a cell-intrinsic manner. CD27 signals promoted the survival of thymic T_reg cells by inhibiting the mitochondrial apoptosis pathway. CD70 was expressed on Aire⁻ and Aire⁺ medullary thymic epithelial cells (mTECs) and on dendritic cells (DCs) in the thymic medulla. CD70 on both mTECs and DCs contributed to T_reg cell development as shown in BM chimera experiments with CD70-deficient mice. In vitro experiments indicated that CD70 on the CD8α⁺ subset of thymic DCs promoted T_reg cell development. Our data suggest that mTECs and DCs form dedicated niches in the thymic medulla, in which CD27–CD70 co-stimulation rescues developing T_reg cells from apoptosis, subsequent to Foxp3 induction by TCR and CD28 signals.