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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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Brain-infiltrating CD8 T cells were not fully activated in this model of antigen-specific CD8 T cell traffic. (A–I) Representative sections 3 d after intrastriatal injection of HA in CL4 mice immunized intradermally with CFA alone (A–C) or HA in CFA (D–F) 5 d previously, and in wild-type littermates receiving 3 million in vitro−activated CL4 CD8 T cells i.v. (G–I). Sections were submitted to immunohistochemistry (brown) for granzyme B (A, D, and G), amyloid precursor protein (B, E, and H), or Luxol Fast Blue histochemistry (C, F, and I). Bars are 60 μm except for the following: A, 30 μm; D, 20 μm; G, 10 μm.
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fig4: Brain-infiltrating CD8 T cells were not fully activated in this model of antigen-specific CD8 T cell traffic. (A–I) Representative sections 3 d after intrastriatal injection of HA in CL4 mice immunized intradermally with CFA alone (A–C) or HA in CFA (D–F) 5 d previously, and in wild-type littermates receiving 3 million in vitro−activated CL4 CD8 T cells i.v. (G–I). Sections were submitted to immunohistochemistry (brown) for granzyme B (A, D, and G), amyloid precursor protein (B, E, and H), or Luxol Fast Blue histochemistry (C, F, and I). Bars are 60 μm except for the following: A, 30 μm; D, 20 μm; G, 10 μm.

Mentions: CD8 T cells infiltrating the brain after intrastriatal injections of HA in CL4 mice were not fully differentiated at any time point, as shown by the lack of granzyme B expression (Fig. 4 A) and lack of tissue damage, as assessed by amyloid precursor protein expression to detect damaged axons (Fig. 4 B) and Luxol Fast Blue histochemistry to detect myelin damage (Fig. 4 C). In contrast, granzyme B expression and axon/myelin damage were seen when CD8 T cells were peripherally activated by immunization with HA in CFA (Fig. 4, D–F) or after in vitro activation (Fig. 4, G–I). CD8 T cells infiltrating the brain after HA injection alone did not proliferate on day 1 (Fig. 1 Q) but started expressing Ki67 at later time points (Fig. 5, A and B). Expression of Ki67 is an indicator of commitment to the cell cycle, and the Ki67 index is the percentage of CD8 T cells expressing this marker; the Ki67 index was 21% on day 2 and peaked at 52% on day 3.


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)

Brain-infiltrating CD8 T cells were not fully activated in this model of antigen-specific CD8 T cell traffic. (A–I) Representative sections 3 d after intrastriatal injection of HA in CL4 mice immunized intradermally with CFA alone (A–C) or HA in CFA (D–F) 5 d previously, and in wild-type littermates receiving 3 million in vitro−activated CL4 CD8 T cells i.v. (G–I). Sections were submitted to immunohistochemistry (brown) for granzyme B (A, D, and G), amyloid precursor protein (B, E, and H), or Luxol Fast Blue histochemistry (C, F, and I). Bars are 60 μm except for the following: A, 30 μm; D, 20 μm; G, 10 μm.
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Related In: Results  -  Collection

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fig4: Brain-infiltrating CD8 T cells were not fully activated in this model of antigen-specific CD8 T cell traffic. (A–I) Representative sections 3 d after intrastriatal injection of HA in CL4 mice immunized intradermally with CFA alone (A–C) or HA in CFA (D–F) 5 d previously, and in wild-type littermates receiving 3 million in vitro−activated CL4 CD8 T cells i.v. (G–I). Sections were submitted to immunohistochemistry (brown) for granzyme B (A, D, and G), amyloid precursor protein (B, E, and H), or Luxol Fast Blue histochemistry (C, F, and I). Bars are 60 μm except for the following: A, 30 μm; D, 20 μm; G, 10 μm.
Mentions: CD8 T cells infiltrating the brain after intrastriatal injections of HA in CL4 mice were not fully differentiated at any time point, as shown by the lack of granzyme B expression (Fig. 4 A) and lack of tissue damage, as assessed by amyloid precursor protein expression to detect damaged axons (Fig. 4 B) and Luxol Fast Blue histochemistry to detect myelin damage (Fig. 4 C). In contrast, granzyme B expression and axon/myelin damage were seen when CD8 T cells were peripherally activated by immunization with HA in CFA (Fig. 4, D–F) or after in vitro activation (Fig. 4, G–I). CD8 T cells infiltrating the brain after HA injection alone did not proliferate on day 1 (Fig. 1 Q) but started expressing Ki67 at later time points (Fig. 5, A and B). Expression of Ki67 is an indicator of commitment to the cell cycle, and the Ki67 index is the percentage of CD8 T cells expressing this marker; the Ki67 index was 21% on day 2 and peaked at 52% on day 3.

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