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-γ (IFN-γ) is essential for preventing reactivation of chronic infection with Toxoplasma gondii in the brain. We examined the role of IFN-γ on lymphocyte and endothelial adhesion molecule expression and T cell recruitment into the brain during chronic infection with T. gondii in IFN-γ knockout (IFN-γ^-/-) 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-γ^-/- mice following infection, there were more VCAM-1⁺ vessels in brains of infected WT than of infected IFN-γ^-/- 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-γ^-/- than WT mice. Treatment of infected IFN-γ^-/- mice with recombinant IFN-γ 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-γ^-/- 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 α4β1 integrin⁺. In adoptive transfer of immune spleen cells, pretreatment of the cells with a monoclonal antibody (mAb) against α4 integrin markedly inhibited recruitment of CD8⁺ T cells into the brain of chronically infected WT mice. These results indicate that IFN-γ-induced expression of endothelial VCAM-1 and its binding to α4β1 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-1ICAM-1 interaction may also be involved in this process.