Understanding the intricate interplay among immune responses and homeostatic cell function in Alzheimer's disease (AD) remains challenging. Here, we present a novel strategy to mitigate AD pathology by directly modulating the immune checkpoint PD-1/PD-L1 signaling pathway in the brain, where elevated levels of microglial PD-1 and astrocytic PD-L1 have been observed. We found that a single intracortical injection of anti-PD-L1 antibody facilitates the infiltration of peripheral immune cells into the brain, including IL-10-secreting Ly6C+ monocytes. Subsequently, this leads to the restoration of microglial homeostatic functions including an increase in P2RY12 expression, which enhances microglial process extension. This cascade of events following anti-PD-L1 injection is crucial for regulating abnormally hyperactive neurons and reducing amyloid-beta plaques. These findings suggest that the direct application of immune checkpoint blockade in the brain could offer a new approach to managing the delicate cell-cell interactions among neurons, glial cells, and peripheral immune cells in the AD brain.

Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic CD8+ T cell responses mediate disease. Although these responses originate in the lymph node, we found that expression of the cytolytic effector molecule granzyme B was restricted to lesional CD8+ T cells in Leishmania-infected mice, suggesting that local cues within inflamed skin induced cytolytic function. Expression of Blimp-1 (Prdm1), a transcription factor necessary for cytolytic CD8+ T cell differentiation, was driven by hypoxia within the inflamed skin. Hypoxia was further enhanced by the recruitment of neutrophils that consumed oxygen to produce ROS and ultimately increased the hypoxic state and granzyme B expression in CD8+ T cells. Importantly, lesions from patients with cutaneous leishmaniasis exhibited hypoxia transcription signatures that correlated with the presence of neutrophils. Thus, targeting hypoxia-driven signals that support local differentiation of cytolytic CD8+ T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as for other inflammatory skin diseases in which cytolytic CD8+ T cells contribute to pathogenesis.

Tau-mediated neurodegeneration is a hallmark of Alzheimer's disease. Primary tauopathies are characterized by pathological tau accumulation and neuronal and synaptic loss. Apolipoprotein E (ApoE)-mediated neuroinflammation is involved in the progression of tau-mediated neurodegeneration, and emerging evidence suggests that the gut microbiota regulates neuroinflammation in an APOE genotype-dependent manner. However, evidence of a causal link between the microbiota and tau-mediated neurodegeneration is lacking. In this study, we characterized a genetically engineered mouse model of tauopathy expressing human ApoE isoforms reared under germ-free conditions or after perturbation of their gut microbiota with antibiotics. Both of these manipulations reduced gliosis, tau pathology, and neurodegeneration in a sex- and ApoE isoform-dependent manner. The findings reveal mechanistic and translationally relevant interrelationships between the microbiota, neuroinflammation, and tau-mediated neurodegeneration.