Advances in Meningeal Immunity
Authors: Rejane Rua, Dorian B. McGavern
Journal: Trends in Molecular Medicine (2018)

The CNS is protected by layers of cells that are collectively referred to as the meninges. Far from being an inert connective tissue, emerging data indicate that the meninges serve as an interface with the periphery and actively contribute to CNS homeostasis and immunity. The meningeal layers have a far more diverse immune repertoire than the CNS parenchyma and are innervated, have lymphatic drainage (dura), contain permeable blood vessels (dura), and support robust inflammatory responses. The meninges serve as a gatekeeper that isolates the brain and spinal cord parenchyma from the periphery. The meninges develop and support immune responses far more readily than the parenchyma, which can both protect and harm the CNS. The meninges are highly innervated, which can influence meningeal immunity and vascular tone. Both sterile and infectious challenges can trigger meningeal inflammation, which results in subsequent degradation of the glial limitans and immune infiltration into the CNS parenchyma. This process can give rise to neurological disorders. Therapeutically, the meninges are far easier to access from the periphery than the CNS parenchyma (especially the dura mater). Modulation of meningeal immunity represents a promising therapeutic target to treat inflammatory neurological disorders and possibly to regulate neural homeostasis. The central nervous system (CNS) is an immunologically specialized tissue protected by a blood–brain barrier. The CNS parenchyma is enveloped by a series of overlapping membranes that are collectively referred to as the meninges. The meninges provide an additional CNS barrier, harbor a diverse array of resident immune cells, and serve as a crucial interface with the periphery. Recent studies have significantly advanced our understanding of meningeal immunity, demonstrating how a complex immune landscape influences CNS functions under steady-state and inflammatory conditions. The location and activation state of meningeal immune cells can profoundly influence CNS homeostasis and contribute to neurological disorders, but these cells are also well equipped to protect the CNS from pathogens. In this review, we discuss advances in our understanding of the meningeal immune repertoire and provide insights into how this CNS barrier operates immunologically under conditions ranging from neurocognition to inflammatory diseases. The central nervous system (CNS) is an immunologically specialized tissue protected by a blood–brain barrier. The CNS parenchyma is enveloped by a series of overlapping membranes that are collectively referred to as the meninges. The meninges provide an additional CNS barrier, harbor a diverse array of resident immune cells, and serve as a crucial interface with the periphery. Recent studies have significantly advanced our understanding of meningeal immunity, demonstrating how a complex immune landscape influences CNS functions under steady-state and inflammatory conditions. The location and activation state of meningeal immune cells can profoundly influence CNS homeostasis and contribute to neurological disorders, but these cells are also well equipped to protect the CNS from pathogens. In this review, we discuss advances in our understanding of the meningeal immune repertoire and provide insights into how this CNS barrier operates immunologically under conditions ranging from neurocognition to inflammatory diseases. The central nervous system (CNS) is protected by several membranes that are collectively referred to as the meninges (see Glossary). Despite serving as a barrier and interface between the CNS and periphery, little is known about the immune composition of the meninges or how meningeal immunity affects the CNS under steady-state and inflammatory conditions. Recent advances in the field of meningeal immunity have begun to reshape our understanding of this compartment and indicate that it plays an important role in directing and coordinating immune traffic throughout the CNS [1Coles J.A. et al.Where are we? The anatomy of the murine cortical meninges revisited for intravital imaging, immunology, and clearance of waste from the brain.Prog. Neurobiol. 2017; 156: 107-148Crossref PubMed Scopus (4) Google Scholar]. Most CNS immune responses begin in the meninges before gaining access to the parenchyma, and emerging data indicate that the meninges are far more supportive than the parenchyma in hosting inflammation [2Filiano A.J. et al.Interactions of innate and adaptive immunity in brain development and function.Brain Res. 2015; 1617: 18-27Crossref PubMed Scopus (30) Google Scholar]. Compared with the CNS parenchyma, the meninges are an under-studied compartment and thought mainly to serve as a protective barrier, yet meningeal immunity can profoundly influence CNS homeostasis and even contribute to neurological disorders. Here, we provide a contemporary view of the meninges, focusing first on its exquisite anatomy and then define meningeal immunity under steady-state and inflammatory conditions. The meninges consist of three cellular layers with different properties: the dura mater, which is adjacent to the skull, the arachnoid mater, and the pia mater, which is the layer just above the brain and spinal cord parenchyma (Figure 1). The dura mater in humans is a dense, tough, collagenous membrane [3Protasoni M. et al.The collagenic architecture of human dura mater.J. Neurosurg. 2011; 114: 1723-1730Crossref PubMed Scopus (0) Google Scholar] that is highly innervated, vascularized, and contains lymphatics [4Absinta M. et al.Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI.Elife. 2017; 6e29738Crossref PubMed Google Scholar]. The arachnoid mater is a barrier that separates the dura mater from the rest of the CNS. Importantly, cells in the arachnoid mater have tight junctions and regulate the transport of molecules, similar to the blood–brain barrier [5Balin B.J. et al.Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey.J. Comp. Neurol. 1986; 251: 260-280Crossref PubMed Google Scholar, 6Yasuda K. et al.Drug transporters on arachnoid barrier cells contribute to the blood-cerebrospinal fluid barrier.Drug Metab. Dispos. 2013; 41: 923-931Crossref PubMed Scopus (25) Google Scholar], although studies in mice have demonstrated that the arachnoid mater is permissive to the passage of molecules (up to 40 kDa) applied to the dura mater [7Roth T.L. et al.Transcranial amelioration of inflammation and cell death after brain injury.Nature. 2014; 505: 223-228Crossref PubMed Scopus (156) Google Scholar]. Beneath the arachnoid mater lies the subarachnoid space, through which cerebrospinal fluid (CSF) flows. This space contains trabeculae and collagen bundles generated by fibroblast-like cells that connect the arachnoid to the pia mater [8Hagan C.E. et al.Nervous system.in: Treuting P.M. Dintzis S. Comparative Anatomy and Histology: A Mouse and Human Atlas. Academic Press, 2012: 339-394Crossref Scopus (7) Google Scholar]. The CSF within this space is important for brain buoyancy and is produced by choroid plexus epithelium. CSF flows through the ventricles as well as subarachnoid spaces and eventually effluxes into the blood (reviewed in [9Spector R. et al.A balanced view of the cerebrospinal fluid composition and functions: focus on adult humans.Exp. Neurol. 2015; 273: 57-68Crossref PubMed Scopus (43) Google Scholar]). Lastly, the pial membrane, which covers the brain and spinal cord parenchyma, is semipermeable to the CSF that flows along penetrating vessels in perivascular spaces (Figure 1) [10Hartman A.L. Normal anatomy of the cerebrospinal fluid compartment.in: Irani D.N. Cerebrospinal Fluid in Clinical Practice. Saunders, 2009: 5-10Crossref Scopus (1) Google Scholar]. Together, the arachnoid and pial membranes are referred to as the leptomeninges, which are relatively thin when compared with the thick dural membrane. Within the CNS parenchyma, the surface-associated astrocytes are juxtaposed to the pial membrane, providing yet another protective barrier referred to as the glial limitans. This structure follows penetrating blood vessels in the CNS parenchyma, with astrocytic endfeet forming a dense and highly charged basement membrane that is permeable to some molecules within the CSF (Figure 1) [11Hannocks M.J. et al.Molecular characterization of perivascular drainage pathways in the murine brain.J. Cereb. Blood Flow Metab. 2017; 38: 669-686Crossref PubMed Scopus (3) Google Scholar]. In rodents, fluorophores (0.8 kDa), fluorescent dextran (3, 10, 70, and 2000 kDa), albumin (45 kDa), and immunoglobulin (150 kDa) injected into the CSF via the cisterna magna are seen in the perivascular spaces along descending pial arteries within a few minutes [11Hannocks M.J. et al.Molecular characterization of perivascular drainage pathways in the murine brain.J. Cereb. Blood Flow Metab. 2017; 38: 669-686Crossref PubMed Scopus (3) Google Scholar, 12Bedussi B. et al.Clearance from the mouse brain by convection of interstitial fluid towards the ventricular system.Fluids Barriers CNS. 2015; 12: 23Crossref PubMed Scopus (16) Google Scholar, 13Iliff J.J. et al.A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta.Sci. Transl. Med. 2012; 4147ra111Crossref PubMed Scopus (824) Google Scholar, 14Smith A.J. et al.Test of the 'glymphatic' hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma.Elife. 2017; 6e27679Crossref PubMed Scopus (4) Google Scholar]. Once within these spaces, some molecules can gradually enter the brain parenchyma in a size-dependent manner. For example, a 0.8 kDa fluorophore injected into the CSF was observed throughout the brain parenchyma 30 min after injection [13Iliff J.J. et al.A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta.Sci. Transl. Med. 2012; 4147ra111Crossref PubMed Scopus (824) Google Scholar], whereas slightly larger molecules (3–10-kDa dextrans) were only able to penetrate 50–100 μm into the parenchyma [12Bedussi B. et al.Clearance from the mouse brain by convection of interstitial fluid towards the ventricular system.Fluids Barriers CNS. 2015; 12: 23Crossref PubMed Scopus (16) Google Scholar, 14Smith A.J. et al.Test of the 'glymphatic' hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma.Elife. 2017; 6e27679Crossref PubMed Scopus (4) Google Scholar]. Even larger molecules (45 and 70 kDa) were detected up to 35 μm below the glia limitans [13Iliff J.J. et al.A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta.Sci. Transl. Med. 2012; 4147ra111Crossref PubMed Scopus (824) Google Scholar, 14Smith A.J. et al.Test of the 'glymphatic' hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma.Elife. 2017; 6e27679Crossref PubMed Scopus (4) Google Scholar], and molecules from 150 to 2000 kDa were found to be completely excluded from the parenchyma and remained in the perivascular spaces [11Hannocks M.J. et al.Molecular characterization of perivascular drainage pathways in the murine brain.J. Cereb. Blood Flow Metab. 2017; 38: 669-686Crossref PubMed Scopus (3) Google Scholar, 12Bedussi B. et al.Clearance from the mouse brain by convection of interstitial fluid towards the ventricular system.Fluids Barriers CNS. 2015; 12: 23Crossref PubMed Scopus (16) Google Scholar, 13Iliff J.J. et al.A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta.Sci. Transl. Med. 2012; 4147ra111Crossref PubMed Scopus (824) Google Scholar, 14Smith A.J. et al.Test of the 'glymphatic' hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma.Elife. 2017; 6e27679Crossref PubMed Scopus (4) Google Scholar]. Based on this size exclusion system, soluble mediators like cytokines (∼10–50 kDa) would only have limited ability to enter and affect the parenchyma under steady-state conditions with the CNS barrier system intact. It should be noted, however, that all the data above are based on injection of fluorescent tracers directly into the CSF. The CSF is produced at a rate of 0.35 μl/min in mice [15Simon M.J. Iliff J.J. Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease.Biochim. Biophys. Acta. 2016; 1862: 442-451Crossref PubMed Scopus (30) Google Scholar]. Injection of additional fluid into CSF above this rate has the potential to cause edema and artefactual intracranial pressures. For example, tracers in the aforementioned studies were injected into the CSF at rates ranging from 0.17 to 2 μl/min. The acute inflammatory response generated by insertion of a needle into the ventricle must also be considered when interpreting these fluorescent tracer studies. Nevertheless, the glial limitans appears to be permissive, in a size-dependent manner, to the passage of at least some molecules. Molecules excluded from parenchymal entry on the basis of size must rely on transport systems. The driving force behind the entry of CSF and small molecules into the parenchyma is unclear. According to the 'glymphatics' theory, fluid is actively pushed from the perivascular spaces along penetrating blood vessels into the CNS parenchyma [13Iliff J.J. et al.A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta.Sci. Transl. Med. 2012; 4147ra111Crossref PubMed Scopus (824) Google Scholar]; however, a more recent study called this theory into question, concluding that the movement of fluid is based instead on simple diffusion [14Smith A.J. et al.Test of the 'glymphatic' hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma.Elife. 2017; 6e27679Crossref PubMed Scopus (4) Google Scholar]. Future studies are required to resolve this discrepancy and determine how the glial limitans regulates entry of molecules from the CSF into the parenchyma. The CNS is one of the most irrigated organs and is perfused via the external and internal branches of the carotid artery (reviewed in [16Cipolla M.J. Anatomy and ultrastructure (Chapter 2).The Cerebral Circulation. Morgan & Claypool Life Sciences, 2009: 3-11Google Scholar]). The external carotid artery gives rise to the anterior, middle and posterior meningeal arteries that irrigate the dura mater and skull. The dural meninges are thus highly perfused by blood vessels, and the vasculature is interwoven with peripheral nerve fibers (Figure 2). Blood to the dura mater is then drained by venous sinuses that empty both dural and cerebral veins (reviewed in [1Coles J.A. et al.Where are we? The anatomy of the murine cortical meninges revisited for intravital imaging, immunology, and clearance of waste from the brain.Prog. Neurobiol. 2017; 156: 107-148Crossref PubMed Scopus (4) Google Scholar]). Vessels within the dura mater contain capillary segments and postcapillary venules capable of supporting immune cell traffic. In addition, dural blood vessels appear to be more responsive to mechanical and chemical stimulation than vessels in the underlying cerebrum. Vasoconstriction of these vessels can be caused by increased luminal pressure, as well as neurotransmitters (e.g., noradrenaline) and neuropeptides (e.g., neuropeptide Y). Vasodilation, by contrast, can be induced by electrical stimulation, neuropeptides (e.g., vasointestinal peptide, calcitonin-gene related peptide, substance P), acetylcholine, histamine, and serotonin (Figure 2) [17Wang X. et al.5-HT7 receptors are involved in neurogenic dural vasodilatation in an experimental model of migraine.J. Mol. Neurosci. 2014; 54: 164-170Crossref PubMed Scopus (3) Google Scholar]. Importantly, dural (unlike pial and cerebral) vessels are fenestrated and open to the passage of relatively large (e.g., 43 kDa) molecules injected into the blood [5Balin B.J. et al.Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey.J. Comp. Neurol. 1986; 251: 260-280Crossref PubMed Google Scholar]. Moreover, their permeability increases even further upon trigeminal nerve stimulation or histamine release (Figures 1 and 2) [18Markowitz S. et al.Neurogenically mediated leakage of plasma protein occurs from blood vessels in dura mater but not brain.J. Neurosci. 1987; 7: 4129-4136Crossref PubMed Google Scholar]. Because of the relative openness of dura vessels, the impermeable arachnoid mater plays a crucial role in preventing entry of blood-derived materials into the CSF. The internal carotid arteries form an anastomotic ring with other arteries at the basis of the skull, called the circle of Willis (reviewed in [16Cipolla M.J. Anatomy and ultrastructure (Chapter 2).The Cerebral Circulation. Morgan & Claypool Life Sciences, 2009: 3-11Google Scholar]). This arterial circle gives rise to the anterior, middle, and posterior cerebral arteries that run along the pial surface of the brain before penetrating the parenchyma to supply blood to the cerebral cortex. Penetrating arterioles become progressively enveloped by astrocytic endfeet after they dive into the parenchyma, which forms part of the blood–brain barrier. Unlike dural blood vessels, the endothelial cells comprising pial vessels are connected by tight junctions and can be divided in two groups: 25% of them have no space between endothelial cells, whereas the other 75% have 2.8 nm-gaps [19Cassella J.P. et al.Development of endothelial paracellular clefts and their tight junctions in the pial microvessels of the rat.J. Neurocytol. 1997; 26: 567-575Crossref PubMed Scopus (19) Google Scholar]. Despite these small gaps, pial vessels under steady-state conditions are relatively impermeable to molecules applied intravenously, such as ferritin (440 kDa), HRP (44 kDa), microperoxidase (1.8 kDa), sodium fluorescein (0.4 kDa), and ionic lanthanum (0.1 kDa) (reviewed in [20Nag S. Pathophysiology of blood-brain barrier breakdown.Methods Mol. Med. 2003; 89: 97-119PubMed Google Scholar]). Pial vessels can respond to vasoactive compounds, although to a much lower extent than dural vessels (reviewed in [1Coles J.A. et al.Where are we? 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Pattern of intracranial and extracranial projections of trigeminal ganglion cells.J. Neurosci. 1986; 6: 2200-2207Crossref PubMed Google Scholar], which might represent a mode of communication across the impermeable arachnoid barrier. Lymphatics were first described within the dura mater in the 18th century [27Mascagni P. Vasorum Lymphaticorum Corporis Humani Historia et Ichnographia. P. Carli, 1787Google Scholar] and again in the 1900s [21Andres K.H. et al.Nerve fibres and their terminals of the dura mater encephali of the rat.Anat. Embryol. (Berl.). 1987; 175: 289-301Crossref PubMed Google Scholar, 28Waggener J.D. Beggs J. The membranous coverings of neural tissues: an electron microscopy study.J. Neuropathol. Exp. Neurol. 1967; 26: 412-426Crossref PubMed Google Scholar], but were more recently 'rediscovered' in mice [29Louveau A. et al.Structural and functional features of central nervous system lymphatic vessels.Nature. 2015; 523: 337-341Crossref PubMed Scopus (771) Google Scholar, 30Aspelund A. et al.A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.J. Exp. Med. 2015; 212: 991-999Crossref PubMed Google Scholar] and humans [4Absinta M. et al.Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI.Elife. 2017; 6e29738Crossref PubMed Google Scholar], which renewed interest in the topic. Because blood vessels in the dura mater are fenestrated, like in most peripheral tissues, it is not surprising that a network of dural lymphatic vessels exist to drain tissue fluid from this compartment into lymph nodes. Intracranial lymphatic vessels run along the dural sinuses and the MMA [29Louveau A. et al.Structural and functional features of central nervous system lymphatic vessels.Nature. 2015; 523: 337-341Crossref PubMed Scopus (771) Google Scholar, 30Aspelund A. et al.A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.J. Exp. Med. 2015; 212: 991-999Crossref PubMed Google Scholar]. In addition, extracranial lymphatic vessels follow cranial nerves that exit through the cribriform plate and the base of the skull [30Aspelund A. et al.A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.J. Exp. Med. 2015; 212: 991-999Crossref PubMed Google Scholar, 31Ma Q. et al.Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice.Nat. Commun. 2017; 81434Crossref PubMed Scopus (7) Google Scholar]. Although it is generally accepted that materials from the CSF and parenchyma can drain into the deep cervical lymph nodes (dCLN), the exact route of transport (as assessed by intrathecally injected tracers) is debated, with some suggesting that CSF tracers can traverse the arachnoid mater and enter the dural lymphatics [29Louveau A. et al.Structural and functional features of central nervous system lymphatic vessels.Nature. 2015; 523: 337-341Crossref PubMed Scopus (771) Google Scholar, 30Aspelund A. et al.A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.J. Exp. Med. 2015; 212: 991-999Crossref PubMed Google Scholar] and others proposing that these tracers exit instead via perineural routes through foramina in the skull bone [31Ma Q. et al.Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice.Nat. Commun. 2017; 81434Crossref PubMed Scopus (7) Google Scholar]. Experimental confounds linked to tracer injection methodology (e.g., disruption of meningeal architecture, inflammation, increased intracranial pressure) indicate that less invasive methods are required to investigate routes of CSF egress. Despite the controversy, the rediscovery of the dural lymphatics has triggered a considerable amount of interest in meningeal architecture and immunology. The meninges, under steady-state conditions, are populated by many different immune cell populations (e.g., macrophages, dendritic cells, innate lymphoid cells (ILCs), mast cells, neutrophils, B cells, and T cells) (Figure 1) [1Coles J.A. et al.Where are we? The anatomy of the murine cortical meninges revisited for intravital imaging, immunology, and clearance of waste from the brain.Prog. 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Med. 2010; 207: 1067-1080Crossref PubMed Scopus (242) Google Scholar], although their exact location (leptomeninges versus dura) and trafficking patterns are not entirely understood. Parabiotic studies have revealed that ∼20% meningeal CD4+ T cells are derived from the blood 2 weeks after the vascular systems between the two animals were equilibrated [36Radjavi A. et al.Dynamics of the meningeal CD4(+) T-cell repertoire are defined by the cervical lymph nodes and facilitate cognitive task performance in mice.Mol. Psychiatry. 2014; 19: 531-533Crossref PubMed Scopus (0) Google Scholar]. In addition, surgical resection of the dCLN led to a small accumulation in meningeal CD4+ T cells (increased from ∼1300 to 1600 T cells) 2 weeks later. Together, these data indicate that CD4+ T cells can traffic from the blood into the meninges, where they likely scan the tissue before entering the dCLN. It was also recently discovered using mass cytometry that T cells are enriched in the CNS of mice upon aging [37Mrdjen D. et al.High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease.Immunity. 2018; 48: 599Abstract Full Text Full Text PDF PubMed Google Scholar]. This increase could be linked to the natural process of neurodegeneration that occurs during aging and/or the cumulative exposure to environmental antigens and microbes. Mice, for example, continually inhale materials through their nose, which may influence immune traffic through relatively open barrier structures like the dura mater. As humans encounter far more environmental antigens and microbes than laboratory rodents, it is not surprising that the T cells found under steady-state in the CSF have a central memory phenotype and express homing molecules that allow them to access secondary lymphoid organs [38Kivisakk P. et al.Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 8389-8394Crossref PubMed Scopus (277) Google Scholar, 39de Graaf M.T. et al.Central memory CD4+ T cells dominate the normal cerebrospinal fluid.Cytom. B Clin. Cytom. 2011; 80: 43-50Crossref PubMed Scopus (0) Google Scholar]. This phenotype is consistent with the notion that T cells circulate from the blood into the meninges and then into secondary lymphoid organs. The importance of T cells in CNS homeostasis emerged in part from the discovery that T cell-deficient mice had an impaired ability to perform in spatial learning and memory tests such as the Morris water maze [40Kipnis J. et al.T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions.Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 8180-8185Crossref PubMed Scopus (228) Google Scholar, 41Brynskikh A. et al.Adaptive immunity affects learning behavior in mice.Brain Behav. Immun. 2008; 22: 861-869Crossref PubMed Scopus (107) Google Scholar, 42Cushman J. et al.Neurobehavioral changes resulting from recombinase activation gene 1 deletion.Clin. Diagn. Lab. Immunol. 2003; 10: 13-18Crossref PubMed Scopus (0) Google Scholar, 43Zarif H. et al.CD8(+) T cells are essential for the effects of enriched environment on hippoca