Importance of IFN-γ-mediated expression of endothelial VCAM-1 on recruitment of CD8+ T cells into the brain during chronic infection with Toxoplasma gondii

Interferon-gamma ( IFN-gamma) is essential for preventing reactivation of chronic infection with Toxoplasma gondii in the brain. We examined the role of IFN-gamma on lymphocyte and endothelial adhesion molecule expression and T cell recruitment into the brain during chronic infection with T. gondii in IFN-gamma knockout ( IFN-gamma(-/-)) 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 IFN-gamma(-/-) mice following infection, there were more VCAM-1(+) vessels in brains of infected WT than of infected IFN-gamma(-/-) 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 IFN-gamma(-/-) than WT mice. Treatment of infected IFN-gamma(-/-) 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 IFN-gamma(-/-) 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 alpha 4 beta 1 integrin(+). In adoptive transfer of immune spleen cells, pretreatment of the cells with a monoclonal antibody (mAb) against alpha 4 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 alpha 4 beta 1 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.