H-2D(b-/-) mice are susceptible to persistent infection by Theiler's virus

Abstract

H-2(b) mice are resistant to persistent infection of the central nervous system by Theiler's virus. They clear the infection 7 to 10 days after intracranial inoculation. Resistance maps to the H-2D gene and not to the H-2K gene and is associated with a potent antiviral cytotoxic T-lymphocyte (CTL) response. We used H-2(b) mice in which the H-2D or the H-2K gene had been inactivated to dissect the respective roles of these genes in resistance. We report that H-2D(-/-) but not H-2K(-/-) mice were susceptible to persistent infection. Furthermore, whereas H-2K(-/-) mice mounted a vigorous virus-specific CTL response, similar to that of control C57BL/6 mice, the CTL response of H-2D(-/-) mice was nil or minimal. Using target cells transfected with the H-2D(b) or the H-2K(b) gene, we showed that the H-2K-restricted CTL response against the virus was minimal in H-2D(-/-) mice. These results demonstrate that the H-2D(b) and H-2K(b) genes play nonredundant roles in the resistance to this persistent infection.

FIG. 1

Longitudinal section of the spinal cord of an H-2D^b−/− mouse, 45 days p.i. with Theiler's virus. Viral antigens were detected by immunoperoxidase staining (arrows). Counterstaining was done with hematoxylin. (A) Magnification, ×270. (B) Magnification, ×431.

FIG. 2

Longitudinal section of the spinal cord, 21 days p.i. with Theiler's virus. Viral antigens were detected by immunoperoxidase staining. Counterstaining was done with hematoxylin. (A) Mild inflammation in the gray matter of a control C57BL/6 mouse, in the absence of viral antigens. Magnification, ×431. (B) Intense inflammation and viral antigens (arrows) in the white matter of an H-2D^b−/− mouse. Magnification, ×270.

FIG. 3

Virus-specific CTL responses in one C57BL/6 mouse (squares) and four individual H-2D^b−/− mice (circles). The target cells were infected (closed symbols) or uninfected (open symbols) C57SV fibroblasts. Effector-to-target ratios were 7:1, 15:1, 30:1, and 60:1.

FIG. 4

Virus-specific CTL responses in one C57BL/6 mouse (squares) and four individual H-2D^b−/− mice (circles). The target cells were infected (closed symbols) or uninfected (open symbols) Ltk⁻ cells transfected with the H-2D^b gene (A) or the H-2K^b gene (B). Effector-to-target ratios were 7:1, 15:1, 30:1, and 60:1.

FIG. 5

Virus-specific CTL responses in C57BL/6 and H-2K^b−/− mice (squares and triangles, respectively). The target cells were infected (closed symbols) or uninfected (open symbols) C57SV fibroblasts.