Pro-cognitive properties of T cells

Abstract

Interactions between the central nervous system and the immune system have been studied primarily in the context of pathology, popularizing the view that interplay between these two systems is inherently detrimental. However, recent experimental data have demonstrated productive neuroimmune interactions that occur under normal physiological conditions. In this Essay, we outline our current understanding of contemporary neuroimmunology, describe a working model of T cell function in support of learning and memory, and offer ideas regarding the selective advantages of immune-mediated effects on brain function.

Figure 1. A schematic representation of the Morris water maze

The Morris water maze is a hippocampus-dependent spatial learning task. Mice are introduced individually into a pool that is 1 m in diameter and filled with opaque water (non-toxic paint). There is a hidden platform just beneath the surface of the water, and extra-maze cues are spread throughout the room to allow the mouse to learn the platform location with respect to visuospatial cues. The ‘acquisition’ portion of the task (that is, the portion in which learning is measured) consists of four trials per day of 60 second duration (or until the platform is found) with 5 minute intervals. On day 1 (usually after 60 seconds of failure to find the platform), mice are placed on the platform and are allowed to stay there for 20 seconds. During subsequent trials and days of acquisition, the distance travelled by the mice to reach the hidden platform and the time taken to reach the platform (that is, the latency) are measured with computerized equipment. After 4 days of acquisition, the platform is removed, and the mice are introduced to a single ‘probe’ trial (measuring memory) in which the time spent in the original platform quadrant of the pool is measured. During the next 2 days (the ‘reversal’ portion of the task), the platform is returned to the pool, but to a location opposite to the original one. Four trials per day are performed to measure the ability of the mice to relearn the modified task; this ability is an indication of memory plasticity. After 2 days of reversal, a ‘visible’ trial is performed, wherein the platform is clearly visible, to ensure that basic behaviour in the water is comparable between strains (not shown).

Figure 2. T cell-competent and T cell-deficient meningeal spaces and their effects on learning behaviour

a | The meninges are a multipartite membrane structure composed of the dura mater, which is in contact with the skull, the arachnoid mater and the pia mater, which is in contact with the brain parenchyma. Cerebrospinal fluid (CSF), within which the majority of meningeal immune cells reside, flows between the arachnoid mater and the pia mater in the subarachnoid space. Meningeal immune cells — including B cells, T cells, dendritic cells (DCs), macrophages, mast cells and granulocytes — are found within the subarachnoid space. Access from blood vessels to the meningeal spaces requires cells to penetrate through the blood–meningeal barrier (not shown). In the pr esence of meningeal T cells, the phenotype of meningeal myeloid cells is kept ‘in check’, and normal cognitive function is ensured. b | In the absence of T cells, the meningeal myeloid cells acquire a pro-inflammatory phenotype, which interferes with learning behaviour.

Figure 3. Brain-derived molecular cues and their targets

A brain that is ‘alert’ as a result of performing cognitive tasks or undergoing minor stress produces numerous molecular mediators that signal to meningeal immune cells, the draining lymph nodes and possibly also lymph node-resident neural cells. These molecular mediators include myelin and neural debris, neurotransmitters and neuropeptides. Neurotransmitters and neuropeptides can interact with different immune cells directly through their specific receptors expressed on the immune cells. Molecular patterns such as myelin and neuronal debris possibly activate meningeal myeloid cells via pattern-recognition receptors (PRRs), as well as being processed by antigen-presenting cells (in the meninges or in the draining lymph nodes), leading to the activation of antigen-specific T cells.

Figure 4. A model for the physiological recall of T cells to support learning behaviour versus a response to a pathogen

a | We propose that, under physiological conditions, cognitive task performance or minor stress results in the release of brain-derived molecular cues from the ‘alert’ brain that trigger a specific T cell response, predominantly resulting in the production of interleukin-4 (IL-4). IL-4-producing T cells are also recalled from the draining deep cervical lymph nodes to the meningeal spaces and maintain meningeal myeloid cells (depicted as macrophages) in an M2, anti-inflammatory state. b | In the presence of a pathogen, the draining lymph nodes receive signals from pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs), which dominate the T cell response regardless of the presence of the brainderived molecular cues. Consequently, pro-inflammatory T cells are recalled to the meninges to fight off pathogens, meningeal myeloid cells adopt an M1, pro-inflammatory state and cognitive function is impaired. PRR, pattern-recognition receptor; TNF, tumour necrosis factor.