Apparent MHC-independent stimulation of CD8⁺ T cells in vivo during latent murine gammaherpesvirus infection

Like EBV-infected humans with infectious mononucleosis, mice infected with the rodent gammaherpesvirus MHV-68 develop a profound increase in the number of CD8⁺ T cells in the circulation. In the mouse model, this lymphocytosis consists of highly activated CD8⁺ T cells strikingly biased toward Vβ4 TCR expression. Moreover, this expansion of Vβ4⁺CD8⁺ T cells does not depend on the MHC haplotype of the infected animal. Using a panel of lacZ-inducible T cell hybridomas, we have detected Vβ4-specific T cell stimulatory activity in the spleens of MHV-68-infected mice. We show that the appearance and quantity of this activity correlate with the establishment and magnitude of latent vital infection. Furthermore, on the basis of Ab blocking studies as well as experiments with MHC class II, β₂-microglobulin (β₂m) and TAP1 knockout mice, the Vβ4-specific T cell stimulatory activity does not appear to depend on conventional presentation by classical MHC class I or class II molecules. Taken together, the data indicate that during latent infection, MHV-68 may express a T cell ligand that differs fundamentally from both conventional peptide Ags and classical viral superantigens.