Capsid-Specific Cytotoxic T Lymphocytes Recognize Three Distinct H-2D^b-Restricted Regions of the BeAn Strain of Theiler's Virus and Exhibit Different Cytokine Profiles

Abstract

The role of virus-specific cytotoxic T lymphocytes (CTL) inBased on cytokine profiles, CTL specific for these subdominant epitopes are Tc2, in contrast to CTL for the immunodominant epitope, which are of the Tc1 type. Interestingly, CTL function towards both of these subdominant epitopes is restricted by the H-2D molecule, despite the fact that these epitopes bind both H-2K and H-2D molecules. This skewing toward an H-2D b -restricted response may confer resistance to TMEVinduced demyelinating disease, which is known to be associated with the H-2D genetic locus.

Anticapsid Immunity Level, Not Viral Persistence Level, Correlates with the Progression of Theiler's Virus-Induced Demyelinating Disease in Viral P1-Transgenic Mice

“…Freshly isolated CNS-infiltrating MNCs were cultured for 6 h in 96-well round-bottom plates in the presence of relevant or control peptides as previously described (35). Allophycocyanin-conjugated anti-CD8 (clone Ly2) or anti-CD4 (clone L3T4) antibody and phycoerythrin-labeled rat monoclonal anti-IFN-␥ (XMG1.2) antibody was used for intracellular cytokine staining.…”

“…Overall, T-cell proliferation levels for the epitopes by splenic and LN CD4 ϩ T cells from B6 P1-Tg mice were only 23 and 12% of the responses by their littermates, indicating that CD4 ϩ T-cell responses to P1 neoself antigens were effectively tolerized. In contrast, CD4 ϩ T-cell responses to capsid epitopes (VP1 233-250 , VP2 74-86 , and VP3 [24][25][26][27][28][29][30][31][32][33][34][35][36][37] ) in SJL P1-Tg mice were as much as 64 to 75% of the responses by their littermates. These results indicate that the Tg expression of the TMEV P1 region induces the weak tolerance of proliferative responses to capsid-specific CD4 ϩ Tcell epitopes in SJL P1-Tg mice, in contrast to the strong tolerance seen in B6 P1-Tg mice.…”

“…At 9 days postimmunization (pi), lymph node (LN) and spleen cells were stimulated with capsid peptides recognized by CD4 ϩ T cells. B6 P1-Tg mice displayed severe unresponsiveness (P Ͻ 0.001) in their proliferative responses to capsid epitopes (VP2 206-220 and VP4 [25][26][27][28][29][30][31][32][33][34][35][36][37][38] ) compared to those from their littermates ( Fig. 2A).…”

“…(A) CNS-infiltrating MNCs isolated from TMEV-infected mice were restimulated with the indicated mixture of CD4 ϩ T-cell-specific epitopes (S mix for cells from B6 mice, VP2 206-220 and VP4 [25][26][27][28][29][30][31][32][33][34][35][36][37][38] ; S mix for cells from SJL mice, VP1 233-250 , VP2 [74][75][76][77][78][79][80][81][82][83][84][85][86] , and VP3 [24][25][26][27][28][29][30][31][32][33][34][35][36][37]. CON represents control cultures similarly incubated with PBS.…”

“…with a smaller magnitude of induction (35). It was previously shown that resistant B6 mice, in the absence of both CD8 ϩ T-cell and antibody responses, develop encephalitis rather than demyelination following infection with TMEV (22).…”