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An antigen-specific pathway for CD8 T cells across the blood-brain barrier.

Galea I, Bernardes-Silva M, Forse PA, van Rooijen N, Liblau RS, Perry VH - J. Exp. Med. (2007)

Bottom Line: This was independent of antigen presentation by perivascular macrophages.Marked reduction of antigen-specific CD8 T cell infiltration was observed after intravenous injection of blocking anti-MHC class I antibody.These results expose a hitherto unappreciated route by which CD8 T cells home onto their cognate antigen behind the BBB: luminal MHC class I antigen presentation by cerebral endothelium to circulating CD8 T cells.

View Article: PubMed Central - PubMed

Affiliation: CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton, UK. I.Galea@soton.ac.uk

ABSTRACT
CD8 T cells are nature's foremost defense in encephalitis and brain tumors. Antigen-specific CD8 T cells need to enter the brain to exert their beneficial effects. On the other hand, traffic of CD8 T cells specific for neural antigen may trigger autoimmune diseases like multiple sclerosis. T cell traffic into the central nervous system is thought to occur when activated T cells cross the blood-brain barrier (BBB) regardless of their antigen specificity, but studies have focused on CD4 T cells. Here, we show that selective traffic of antigen-specific CD8 T cells into the brain occurs in vivo and is dependent on luminal expression of major histocompatibility complex (MHC) class I by cerebral endothelium. After intracerebral antigen injection, using a minimally invasive technique, transgenic CD8 T cells only infiltrated the brain when and where their cognate antigen was present. This was independent of antigen presentation by perivascular macrophages. Marked reduction of antigen-specific CD8 T cell infiltration was observed after intravenous injection of blocking anti-MHC class I antibody. These results expose a hitherto unappreciated route by which CD8 T cells home onto their cognate antigen behind the BBB: luminal MHC class I antigen presentation by cerebral endothelium to circulating CD8 T cells. This has implications for a variety of diseases in which antigen-specific CD8 T cell traffic into the brain is a beneficial or deleterious feature.

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The role of endothelial MHC class I in antigen-specific CD8 T cell infiltration into the brain. (A–F) Immunohistochemistry (brown) for MHC class I (A–E) and CD8 (F) in naive striatum (A) and striatum from CL4 mice injected with Cw3 (B) or HA (C–F). E and F show serial sections. (G–I) Immunohistochemistry (brown) for biotinylated IgG 3 d after intrastriatal HA injection (day 0) in CL4 mice receiving i.v. biotinylated anti–MHC class I antibody (H and I) or control biotinylated IgG (G) on day 2. (J) CL4 mice injected with HA intrastriatally received an i.v. bolus of blocking anti–MHC class I antibody or control IgG on day 2 and were perfused on day 3. There was a 76% reduction (95% CI = −139.5 to −40.0) in CD8 T cell infiltration (two-tailed Student's t test, P = 0.002). (K–M) High power confocal micrographs after double immunofluorescence on striatum for biotin (green in K) and γ1-laminin (red in L) (merged in M) 3 d after intrastriatal HA injection (day 0) in CL4 mice receiving i.v. biotinylated anti–MHC class I antibody on day 2. Bars: K–M, 10 μm; E and F, 30 μm; A–C, 50 μm; G and H, 100 μm; D and I, 200 μm.
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fig3: The role of endothelial MHC class I in antigen-specific CD8 T cell infiltration into the brain. (A–F) Immunohistochemistry (brown) for MHC class I (A–E) and CD8 (F) in naive striatum (A) and striatum from CL4 mice injected with Cw3 (B) or HA (C–F). E and F show serial sections. (G–I) Immunohistochemistry (brown) for biotinylated IgG 3 d after intrastriatal HA injection (day 0) in CL4 mice receiving i.v. biotinylated anti–MHC class I antibody (H and I) or control biotinylated IgG (G) on day 2. (J) CL4 mice injected with HA intrastriatally received an i.v. bolus of blocking anti–MHC class I antibody or control IgG on day 2 and were perfused on day 3. There was a 76% reduction (95% CI = −139.5 to −40.0) in CD8 T cell infiltration (two-tailed Student's t test, P = 0.002). (K–M) High power confocal micrographs after double immunofluorescence on striatum for biotin (green in K) and γ1-laminin (red in L) (merged in M) 3 d after intrastriatal HA injection (day 0) in CL4 mice receiving i.v. biotinylated anti–MHC class I antibody on day 2. Bars: K–M, 10 μm; E and F, 30 μm; A–C, 50 μm; G and H, 100 μm; D and I, 200 μm.

Mentions: Because an antigen-presenting process was suspected to play an important role in CD8 T cell infiltration, we studied the expression of MHC class I by immunohistochemistry on days 0, 0.5, 1, 1.5, 2, 2.5, 3, 5, and 7 after intrastriatal injection of HA in CL4 mice (at least n = 3 for each time point). In naive uninjected animals, a very low basal level of MHC class I expression by endothelium was noted (Fig. 3 A). Constitutive MHC class I expression was slightly up-regulated upon injection of Cw3 (Fig. 3 B). After injection of HA, there was dramatic up-regulation of MHC class I by endothelial cells, peaking at day 3 (Fig. 3 C). This up-regulation was largely limited to the site of antigen deposition (Fig. 3 D) and coinciding temporally and spatially with peak CD8 T cell infiltration. CD8 T cells were seen in association with MHC class I+ blood vessels at various stages of infiltration (Fig. 3, E and F). This raised the possibility that CD8 T cell traffic into the brain was facilitated by recognition of the cognate antigen presented by cerebral endothelial cells. For this to occur, however, antigen presentation by cerebral endothelial MHC class I would have to be luminal.


An antigen-specific pathway for CD8 T cells across the blood-brain barrier.

Galea I, Bernardes-Silva M, Forse PA, van Rooijen N, Liblau RS, Perry VH - J. Exp. Med. (2007)

The role of endothelial MHC class I in antigen-specific CD8 T cell infiltration into the brain. (A–F) Immunohistochemistry (brown) for MHC class I (A–E) and CD8 (F) in naive striatum (A) and striatum from CL4 mice injected with Cw3 (B) or HA (C–F). E and F show serial sections. (G–I) Immunohistochemistry (brown) for biotinylated IgG 3 d after intrastriatal HA injection (day 0) in CL4 mice receiving i.v. biotinylated anti–MHC class I antibody (H and I) or control biotinylated IgG (G) on day 2. (J) CL4 mice injected with HA intrastriatally received an i.v. bolus of blocking anti–MHC class I antibody or control IgG on day 2 and were perfused on day 3. There was a 76% reduction (95% CI = −139.5 to −40.0) in CD8 T cell infiltration (two-tailed Student's t test, P = 0.002). (K–M) High power confocal micrographs after double immunofluorescence on striatum for biotin (green in K) and γ1-laminin (red in L) (merged in M) 3 d after intrastriatal HA injection (day 0) in CL4 mice receiving i.v. biotinylated anti–MHC class I antibody on day 2. Bars: K–M, 10 μm; E and F, 30 μm; A–C, 50 μm; G and H, 100 μm; D and I, 200 μm.
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fig3: The role of endothelial MHC class I in antigen-specific CD8 T cell infiltration into the brain. (A–F) Immunohistochemistry (brown) for MHC class I (A–E) and CD8 (F) in naive striatum (A) and striatum from CL4 mice injected with Cw3 (B) or HA (C–F). E and F show serial sections. (G–I) Immunohistochemistry (brown) for biotinylated IgG 3 d after intrastriatal HA injection (day 0) in CL4 mice receiving i.v. biotinylated anti–MHC class I antibody (H and I) or control biotinylated IgG (G) on day 2. (J) CL4 mice injected with HA intrastriatally received an i.v. bolus of blocking anti–MHC class I antibody or control IgG on day 2 and were perfused on day 3. There was a 76% reduction (95% CI = −139.5 to −40.0) in CD8 T cell infiltration (two-tailed Student's t test, P = 0.002). (K–M) High power confocal micrographs after double immunofluorescence on striatum for biotin (green in K) and γ1-laminin (red in L) (merged in M) 3 d after intrastriatal HA injection (day 0) in CL4 mice receiving i.v. biotinylated anti–MHC class I antibody on day 2. Bars: K–M, 10 μm; E and F, 30 μm; A–C, 50 μm; G and H, 100 μm; D and I, 200 μm.
Mentions: Because an antigen-presenting process was suspected to play an important role in CD8 T cell infiltration, we studied the expression of MHC class I by immunohistochemistry on days 0, 0.5, 1, 1.5, 2, 2.5, 3, 5, and 7 after intrastriatal injection of HA in CL4 mice (at least n = 3 for each time point). In naive uninjected animals, a very low basal level of MHC class I expression by endothelium was noted (Fig. 3 A). Constitutive MHC class I expression was slightly up-regulated upon injection of Cw3 (Fig. 3 B). After injection of HA, there was dramatic up-regulation of MHC class I by endothelial cells, peaking at day 3 (Fig. 3 C). This up-regulation was largely limited to the site of antigen deposition (Fig. 3 D) and coinciding temporally and spatially with peak CD8 T cell infiltration. CD8 T cells were seen in association with MHC class I+ blood vessels at various stages of infiltration (Fig. 3, E and F). This raised the possibility that CD8 T cell traffic into the brain was facilitated by recognition of the cognate antigen presented by cerebral endothelial cells. For this to occur, however, antigen presentation by cerebral endothelial MHC class I would have to be luminal.

Bottom Line: This was independent of antigen presentation by perivascular macrophages.Marked reduction of antigen-specific CD8 T cell infiltration was observed after intravenous injection of blocking anti-MHC class I antibody.These results expose a hitherto unappreciated route by which CD8 T cells home onto their cognate antigen behind the BBB: luminal MHC class I antigen presentation by cerebral endothelium to circulating CD8 T cells.

View Article: PubMed Central - PubMed

Affiliation: CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton, UK. I.Galea@soton.ac.uk

ABSTRACT
CD8 T cells are nature's foremost defense in encephalitis and brain tumors. Antigen-specific CD8 T cells need to enter the brain to exert their beneficial effects. On the other hand, traffic of CD8 T cells specific for neural antigen may trigger autoimmune diseases like multiple sclerosis. T cell traffic into the central nervous system is thought to occur when activated T cells cross the blood-brain barrier (BBB) regardless of their antigen specificity, but studies have focused on CD4 T cells. Here, we show that selective traffic of antigen-specific CD8 T cells into the brain occurs in vivo and is dependent on luminal expression of major histocompatibility complex (MHC) class I by cerebral endothelium. After intracerebral antigen injection, using a minimally invasive technique, transgenic CD8 T cells only infiltrated the brain when and where their cognate antigen was present. This was independent of antigen presentation by perivascular macrophages. Marked reduction of antigen-specific CD8 T cell infiltration was observed after intravenous injection of blocking anti-MHC class I antibody. These results expose a hitherto unappreciated route by which CD8 T cells home onto their cognate antigen behind the BBB: luminal MHC class I antigen presentation by cerebral endothelium to circulating CD8 T cells. This has implications for a variety of diseases in which antigen-specific CD8 T cell traffic into the brain is a beneficial or deleterious feature.

Show MeSH
Related in: MedlinePlus