NK Cells, ILC1 Affect Mouse Memory

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Summary

In this study examining adult mice, researchers identified that the meningeal dura layer contains specific immune cells, namely natural killer cells and innate lymphoid cells, that play pivotal roles in the communication between the brain and the immune system. These cells produce substances like interferon-γ and acetylcholine, which have profound effects on brain balance, including the modification of neuronal signals and neurotransmitter concentrations. To delve deeper, interferon-γ is intricately linked to the creation of non-spatial memories and the regulation of certain neurotransmission activities in specific brain neurons. On the other hand, acetylcholine seems to be a key player in managing brain circuits related to anxiety behaviors. Overall, this study offers valuable insights into the interplay between the immune system and the brain's normal operations.

Research Criteria

The article focuses on the role of natural killer (NK) cells and innate lymphoid cells (ILC) 1 in modulating homeostatic functions within the brain. The study demonstrates that these cells shape synaptic neuronal transmission and influence mouse behavior.

Fig.1 Experimental design¹.

Sample Type

Cells sorted from the meninges of the mice.

Result—Meningeal-Resident NK Cells and ILC1 Transcriptional Landscape

In an intricate exploration of the meningeal cellular landscape, researchers meticulously delineated the transcriptional profiles of CD3−/NK1.1+ NK cells and ILC1, shedding light on their potential interactions with the brain. Utilizing single-cell RNA-sequencing, they discerned distinct NK cell clusters and a singular ILC1 cluster, each manifesting unique gene signatures. Notably, the meningeal and splenic NK cells and ILC1 exhibited divergent expression patterns for chemokine receptors and adhesion molecules, hinting at disparate homing mechanisms. Within the meninges, NK cells and ILC1 predominantly expressed Cxcr4, whereas Cxcr6 was exclusive to ILC1. These cells' entry into the CNS, especially post-damage, might be orchestrated by specific chemokine receptor signaling. Additionally, the meningeal NK cells were enriched in transcription factors Irf8 and Eomes, while their ILC1 counterparts predominantly expressed Rora. The observed transcriptional disparities between meningeal and peripheral cells might be attributed to varying tissue origins, innate lymphocyte plasticity, or potentially underscore distinct functional roles of meningeal cells, warranting further investigation.

Fig.2 The transcriptome of meningeal NK cells and ILC1¹.

Result—The Involvement of NK Cells and ILC1 in Mouse Behavior

In a meticulous exploration of the influence of ILC1/NK cells on murine cerebral functions, researchers administered the NK1.1 antibody to C57BL/6 mice, a strain where NK cells notably coincide with ILC1 and NKT in expressing NK1.1 and NKp46 markers. This intervention, while not significantly altering T cell differentiation or peripheral frequency, did modify the frequency of meningeal CD8+ T cells. Behavioral assessments of these treated mice revealed a marked decrease in anxiety-related behavior and a discernible impairment in non-spatial memory, hinting at potential cortical and hippocampal anomalies. Specifically, the absence of NK1.1+ cells led to heightened exploration in open spaces and augmented exploratory behavior, without any associated motor activity aberrations. Furthermore, these mice displayed deficits in both short-term and long-term memory tasks. Parallel treatments with antibodies against the integrin very-late antigen 4 (VLA4) yielded similar behavioral outcomes. Collectively, the findings underscore the pivotal role of innate immune CD3−/NK1.1+ cells in modulating mouse behavior, particularly in the realms of anxiety response and non-spatial memory.

Fig.3 NK cells and ILC1 play a role in mouse behavior¹.

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Reference

1. Garofalo, Stefano, et al. "Natural killer cells and innate lymphoid cells 1 tune anxiety-like behavior and memory in mice via interferon-γ and acetylcholine." Nature Communications 14.1 (2023): 3103.