This finding points to a role for the peripheral adaptive immune system in supporting brain function, rather than suggesting a role for Rag1 in the maintenance of CNS homeostasis. Members of the Toll-like receptor TLR family were recently shown to be expressed in the nervous system by all major cell types Okun et al.

TLRs are a class of pattern recognition receptors expressed on virtually all immune-cell types and known to recognize not only conserved molecular patterns found on pathogens but also endogenous danger signals.

Studies on mice deficient in various TLRs have shown that TLR signaling can affect the proper functioning of the nervous system both positively and negatively, though it is not yet possible to conclude whether such maintenance of nervous system activity is a function of signaling in the brain, in the periphery, or both.

For example, TLR2-knockout mice show impaired differentiation of neural progenitors in the hippocampus, where more neural progenitor cells differentiate into astrocytes than into neurons, pointing to TLR2 as supportive of adult neurogenesis Rolls et al.

On the other hand, TLR4 signaling seems to be a negative regulator of neurogenesis, as TLR4-deficient mice exhibit increased neural progenitor proliferation in the hippocampus, as well as skewed neuronal differentiation Rolls et al.

Investigation of the role of TLR3 signaling in cognitive function revealed that TLR3-knockout mice show generally better memory performance and less anxiety than their wild-type counterparts Okun et al. All in all, the possible roles of TLRs in supporting nervous system homeostasis are only now beginning to be explored, and more detailed studies are necessary in order to understand the specifics of their functioning.

As indicated by the phenotypes of Rag1 - and Rag2 -knockout mice, as well as by the plethora of studies of cognitive performance during infection, the state of the peripheral immune system can greatly influence nervous system functioning.

Adult neurogenesis is a process that has been investigated in the context of numerous types of immune system disruptions. The regulatory presence of an adaptive immune system is necessary for maintenance of adult neurogenesis.

Mice with severe combined immunodeficiency SCID and nude mice, which are deprived, respectively, of all lymphocytes and of T cells, show impairments in neurogenesis, and T-cell replenishment in these mice rescues their phenotype Ziv et al.

Interestingly, transgenic mice with T cells specific for the auto-antigen myelin basic protein exhibit increased neurogenesis, whereas neurogenesis in transgenic mice with T cells specific for an irrelevant antigen ovalbumin is decreased Ziv et al.

These observations suggest that specific interactions between the nervous and immune systems contribute to normal brain function. Mast cells, an immune cell classically associated with allergic responses, are also important for supporting adult neurogenesis Nautiyal et al.

Mast cells are resident in and around the hippocampus and secrete serotonin. From this location they appear to play a role in maintaining the neurogenic niche, since treatment with fluoxetine, a selective inhibitor of serotonin reuptake, abolishes the differences in neurogenesis between mice deficient in mast cells and their heterozygotic littermates Nautiyal et al.

Immune deficiency in mice is often accompanied by cognitive impairment Kipnis et al. As with neurogenesis, replenishment of the immune system by adoptive transfer of wild-type splenocytes or by bone marrow reconstitution also improves the learning ability of SCID and nude mice in MWM, Barnes maze and radial arm water maze Brynskikh et al.

We have recently identified the meningeal membranes surrounding the brain as an important site of the immune response that occurs during learning Derecki et al. When mice are exposed to a learning task, T cells migrate to the meninges and become activated there.

Moreover, the myeloid cells in the meninges become skewed toward an M2 or alternatively activated, also regarded as tissue building and anti-inflammatory phenotype. Interference with the migration of T cells, or genetic deletion of IL-4 , results in a proinflammatory M1 classically activated and inflammatory [ Yirmiya and Goshen ] skew of the myeloid cells in the meninges Belmaker and Agam ; Derecki et al.

In view of these findings, it is tempting to speculate that the adaptive immune system supports cognition by keeping the meningeal innate system in check and preventing inflammation in response to learning-associated stress Fig. Schwartz and colleagues have also identified the choroid plexus as an important site of neuroimmune interactions Baruch et al.

Interestingly, the T cell repertoire in the choroid plexus seems to be enriched in CNS-reactive cells Baruch and Schwartz , leading to the idea that autoimmune cells are important in modulating the nervous system milieu to support homeostasis Kipnis et al.

This argument is also supported by the fact that transgenic mice with CNS-antigen specific T cells also show enhanced cognition, in addition to neurogenesis in subgranular and subventricular zones Ziv et al. Working model of the immune response during a cognitive task.

Under homeostatic conditions, the meningeal spaces are surveyed for potential disturbances by resident myeloid cells, as well as circulating white blood cells including monocytes and T cells.

During an acute cognitive task performance, such as Morris water maze, circulating immune cells can be activated by peripheral danger signals the identity of which is yet to be determined, but potentially corticosterone and catecholamines , which are released in response to the stress that the task involves.

In a wild-type mouse, activated T cells and monocytes infiltrate the meninges and mount a homeostatic type-2 immune response, releasing tissue-building cytokines such as IL-4 and IL In SCID mice that lack the adaptive branch of the immune system no mature T and B cells , nonregulated inflammatory monocytes initiate a type 1 inflammatory response, with the release of inflammatory cytokines such as TNFα.

This review presents evidence for the numerous points of communication between the nervous and the immune systems, and focuses on the consequent implication that a normal functioning immune system is critical in supporting cognitive function.

The relationship between these systems, however, is a mutual one. For example, sympathetic innervation of the bone marrow is required for recruitment of immune cells from the hematopoietic reservoir during infection Katayama et al.

On the other hand, neuronal control through the vagus nerve serves to suppress inflammation in response to endotoxin Borovikova et al. Therefore even when it appears that the nervous system is merely a victim of a flared immune system, the two systems maintain a constant dialogue in the attempt to restore homeostasis.

Although numerous studies now support connections between the nervous and immune systems in models of infection and injury Steinman ; Aaltonen et al. Most of the evidence for immune support in learning comes from whole-body knockout of certain molecules, making it difficult to distinguish cell-specific or developmental effects.

Moreover, more research needs to be devoted to maintenance of the physiological concentrations of tested molecules so that conclusions can be drawn about phenomena in vivo. It often happens that the changes occurring in the body during development or learning are so subtle, and the conditions under which processes are modeled in vitro so extreme, that the relevance of conclusions obtained from in vitro studies is questionable.

We thank Shirley Smith for editing the manuscript. We thank the members of the Kipnis lab for their valuable comments during multiple discussions of this work. This work was primarily supported by a grant from the National Institute on Aging, NIH AG award to J.

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Learning and memory … and the immune system Ioana Marin and Jonathan Kipnis 1 Center for Brain Immunology and Glia BIG , Department of Neuroscience, Neuroscience Graduate Program, School of Medicine, University of Virginia, Charlottesville, Virginia , USA.

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Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Inflammatory bowel disease. Regulation of gut homeostasis by adaptive immune cells.

Role of the innate immune system in gut homeostasis. Regulation of intestinal immune responses by microflora.

Journal Article. Regulation of intestinal homeostasis by innate and adaptive immunity. Hisako Kayama , Hisako Kayama. Oxford Academic. Kiyoshi Takeda. Split View Views. Select Format Select format. ris Mendeley, Papers, Zotero. enw EndNote. bibtex BibTex. txt Medlars, RefWorks Download citation.

Permissions Icon Permissions. Close Navbar Search Filter International Immunology This issue Immunology Books Journals Oxford Academic Enter search term Search. Abstract The intestine is a unique tissue where an elaborate balance is maintained between tolerance and immune responses against a variety of environmental factors such as food and the microflora.

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