title: Importance of IFN-gamma-mediated expression of endothelial VCAM-1 on recruitment of CD8+ T cells into the brain during chronic infection with Toxoplasma gondii.
abstract: Interferon-gamma (IFNgamma) is essential for preventing reactivation of chronic infection with Toxoplasma gondii in the brain. We examined the role of IFNgamma on lymphocyte and endothelial adhesion molecule expression and T cell recruitment into the brain during chronic infection with T. gondii in IFNgamma knockout (IFNgamma(-/-)) and wild-type (WT) mice. Although the number of cerebral vessels expressing intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) increased in both WT and IFNgamma(-/-) mice following infection, there were more VCAM-1(+) vessels in brains of infected WT than of infected IFNgamma(-/-) mice; in contrast, numbers of ICAM-1(+) vessels did not differ between strains. We did not detect endothelial E-selectin, P-selectin, MAdCAM-1, or PNAd in any of the brains. Significantly fewer CD8(+) T cells were recruited into brains of infected IFNgamma(-/-) than WT mice. Treatment of infected IFNgamma(-/-) mice with recombinant IFN-gamma restored the expression of VCAM-1 on their cerebral vessels and recruitment of CD8(+) T cells into their brains, confirming an importance of this cytokine for upregulation of VCAM-1 expression and CD8(+) T cell trafficking. In infected WT and IFNgamma(-/-) animals, almost all cerebral CD8(+) T cells were lymphocyte function-associated antigen-1 (LFA-1)(high), CD44(high), and CD62L(neg), and approximately 38% were alpha4beta1 integrin(+). In adoptive transfer of immune spleen cells, pretreatment of the cells with a monoclonal antibody (mAb) against alpha4 integrin markedly inhibited recruitment of CD8(+) T cells into the brain of chronically infected WT mice. These results indicate that IFN-gamma-induced expression of endothelial VCAM-1 and its binding to alpha4beta1 integrin on CD8(+) T cells is important for recruitment of the T cells into the brain during the chronic stage of T. gondii infection, although LFA-1/ICAM-1 interaction may also be involved in this process.
authors.affiliation: Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Xisheng
authors.initials: X
authors.lastname: Wang
authors.forename: Sara A
authors.initials: SA
authors.lastname: Michie
authors.forename: Baohui
authors.initials: B
authors.lastname: Xu
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002465:Cell Movement; D004727:Endothelium / Q000378:metabolism*; D005260:Female; D039041:Integrin alpha4beta1 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D039041:Integrin alpha4beta1; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma