Quantitative, not qualitative, differences in CD8⁺ T cell responses to Theiler's murine encephalomyelitis virus between resistant C57BL/6 and susceptible SJL/J mice

Abstract

Theiler's murine encephalomyelitis virus (TMEV) infection of the CNS induces an immunemediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis. However, it is not yet clear what immunological parameters determine the susceptibility of SJL/J mice compared to resistant mice. We have here compared the TMEV-specific CD8 + T cell responses in highly susceptible SJL/J mice with those of highly resistant C57BL/6 mice. Our results clearly indicate that the levels of initial responses of infiltrating CD8 + T cells to viral capsid proteins are higher in resistant C57BL/6 mice compared to susceptible SJL/J mice. However, the level of virus-specific CD8 + T cells was much more rapidly reduced in resistant C57BL/6, resulting in a higher CD8 + T cell level in SJL/J mice later in viral infection. The activation states, cytokine production, as well as the cytolytic function of the CD8 + T cells were similar to each other in these mice. These results suggest that an initial induction of a vigorous CD8 + T cell response to TMEV is critically important for the resistance to virally induced demyelinating disease.

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

“…ϩ T-cell responses to minor epitopes (VP3 110-120 and VP3 [165][166][167][168][169][170][171][172][173] ) in the CNS were low (Ͻ5%) in both B6 P1-Tg mice and their littermates throughout the course of viral infection (data not shown), as previously shown for TMEV-infected B6 mice (36). Thus, only CD8 ϩ T cells reactive to the predominant VP2 121-130 epitope were further analyzed.…”

“…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).…”

“…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.…”

“…(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.…”

“…In addition, a recent study has indicated that the level of virusspecific CD8 ϩ T cells in the CNS of susceptible SJL mice is significantly lower than that of resistant B6 mice in the early stages of viral infection, again strongly suggesting that CD8 ϩ T cells play a protective role (36). Although CD4 ϩ T-cell-mediated immune responses are considered pathogenic (16,57), virus-specific CD4 ϩ T cells also may provide protection by contributing to viral clearance and limiting viral replication during the early stages of viral infection (6,9).…”