Prevalent Class I-Restricted T-Cell Response to the Theiler’s Virus Epitope D b :VP2 121–130 in the Absence of Endogenous CD4 Help, Tumor Necrosis Factor Alpha, Gamma Interferon, Perforin, or Costimulation through CD28

Abstract

ABSTRACT C57BL/6 mice mount a cytotoxic T-lymphocyte (CTL) response against the Daniel’s strain of Theiler’s murine encephalomyelitis virus (TMEV) 7 days after infection and do not develop persistent infection or the demyelinating syndrome similar to multiple sclerosis seen in susceptible mice. The TMEV capsid peptide VP2 121–130 sensitizes H-2D b + target cells for killing by central-nervous-system-infiltrating lymphocytes (CNS-ILs) isolated from C57BL/6 mice infected intracranially. D b :VP2 121–130 peptide tetramers were used to stain CD8 + CNS-ILs, revealing that 50 to 63% of these cells bear receptors specific for VP2 121–130 presented in the context of D b . No T cells bearing this specificity were found in the cervical lymph nodes or spleens of TMEV-infected mice. H-2 b mice lacking CD4, class II, gamma interferon, or CD28 expression are susceptible to persistent virus infection but surprisingly still generate high frequencies of CD8 + , D b :VP2 121–130 -specific T cells. However, CD4-negative mice generate a lower frequency of D b :VP2 121–130 -specific T cells than do class II negative or normal H-2 b animals. Resistant tumor necrosis factor alpha receptor I knockout mice also generate a high frequency of CD8 + CNS-ILs specific for D b :VP2 121–130 . Furthermore, normally susceptible FVB mice that express a D b transgene generate D b :VP2 121–130 -specific CD8 + CNS-ILs at a frequency similar to that of C57BL/6 mice. These results demonstrate that VP2 121–130 presented in the context of D b is an immunodominant epitope in TMEV infection and that the frequency of the VP2 121–130 -specific CTLs appears to be independent of several key inflammatory mediators and genetic background but is regulated in part by the expression of CD4.