Differential generation of class I H‐2D‐ versus H‐2K‐restricted cytotoxicity against a demyelinating virus following central nervous system infection

Abstract

Despite the fact that both H-2K and D molecules are up-regulated in the central nervous system (CNS) following Theiler's murine encephalomyelitis virus (TMEV) infection, resistance in this virus model of multiple sclerosis maps exclusively to D. To address this paradox, we examined the ability of the K and D molecules to present viral antigens to cytotoxic T lymphocytes (CTL). Whereas no virus-specific CTL were detected in the CNS of susceptible Bl0.Q and BIO.S mice 7 days post-infection, D-restricted CTL were identified readily in the CNS of resistant B10 animals. There was no evidence of K-restricted CTL in the CNS of B10 mice at day 7 post-infection. The presence of both K-and Drestricted virus-specific CTL in the spleen of immunized B10 mice demonstrates that the exclusive use of D molecules by CTL in the CNS of mice 7 days postinfection is not due to the inability of the K molecules to present viral peptides to lymphocytes. We conclude that the prominent role of the D locus in determining resistance or susceptibility to TMEV-induced demyelination is determined by factors governing the regulation of the immune response, and not by the presence or absence of CTL precursors capable of recognizing viral peptides presented by the K and D antigen-presenting molecules, or by differences in the ability of the K and D molecules to present viral peptides.

H-2Db−/−Mice Are Susceptible to Persistent Infection by Theiler's Virus

“…Although we did not compare the H-2D bϪ/Ϫ and SJL/J strains in the same experiment, the level of viral RNA in the former, 45 days p.i., was lower, and there was more variation between individuals, than what we routinely observe in the latter. This difference might be due to the existence of several susceptibility loci which are found in only the SJL/J strain (8) (6,11,12,15). The fact that, in the experiments reported here, resistance is associated with such a virus-specific CTL response supports this conclusion.…”

Transgenic Expression of Theiler's Murine Encephalomyelitis Virus Genes inH-2bMice Inhibits Resistance to Virus-Induced Demyelination

“…Transgenic expression of LP, VP1, or RP in transfected C57SV cell lines was below the level necessary for fluorescence-activated cell sorter or Western blotting detection. However, these transfected cells served as excellent targets for cytotoxic lymphocyte responses (10,11). We conclude that even though the levels of expression by these transgenes were low, they were sufficient for the transgenes to serve as excellent targets for CD8 ϩ T cells.…”

“…b and H-2D b cells were transfected with region I, II, and III transgenes to function as targets for cytotoxic lymphocyte assays (10,11). We demonstrated virus-specific cytotoxicity of CNSinfiltrating lymphocytes (CNS-ILs) to capsid proteins encoded by LP and VP1, but not RP, which were exclusively H-2D b restricted.…”

“…Preimmunization with VP1 or VP2 protein protects susceptible mice from development of demyelination, whereas immunization with VP3 does not (32), suggesting that an immune response to VP1 and VP2 proteins is beneficial. In susceptible mice, antibody epitopes have been shown to be located in the VP1 protein (VP1 [12][13][14][15][16][17][18][19][20][21][22][23][24][25] , VP1 146-160 , and VP1 262-276), VP2 protein (VP2 [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and VP2 165-179 ), and VP3 protein (VP3 [24][25][26][27][28][29][30][31][32][33][34][35][36][37] ) (7,9). In summary, the data provide support for the hypothesis that the immune responses to capsid antigens of TMEV contribute to the pathogenesis of TMEV infection.…”

Gamma Interferon Is Critical for Neuronal Viral Clearance and Protection in a Susceptible Mouse Strain following Early Intracranial Theiler's Murine Encephalomyelitis Virus Infection

“…In particular, soluble factors such as alpha/beta interferon (IFN-␣/␤) (39) are required for the up-regulation of MHC in most CNS cells, including neurons. Cytotoxic T-cell responses in brain infiltrating mononuclear inflammatory cells have been demonstrated (23,24,25,28) and have been shown to participate in viral clearance. However, the consequences to the CNS are a "double-edged sword."…”