Identification of quantitative trait loci controlling activation of TRBV4 CD8⁺ T cells during murine γ-herpesvirus-induced infectious mononucleosis

Abstract

The murine γ-herpesvirus, MHV-68, shares important biological and genetic features with the human γ-herpesvirus, Epstein-Barr virus. Following intranasal infection, mice develop an infectious mononucleosis-like syndrome accompanied by increased numbers of activated CD8⁺ T cells in the blood. A consistent feature of the CD8⁺ T-cell activation is a marked increase in the frequency of cells expressing a TRBV4⁺ T-cell receptor. Previous studies suggested that the magnitude of TRBV4 expansion varied significantly among mouse strains, and was influenced by both MHC and non-MHC genes. Detailed analysis of strains with high (C57BL/6) or low (DBA/2) TRBV4 CD8⁺ T-cell expansion showed that differences in the degree of expansion were not a consequence of variation in genetic susceptibility to the viral infection. Rather, the magnitude of the TRBV4 CD8⁺ T-cell expansion correlated with differences in expression of the unidentified stimulatory ligand on activated, latently infected B cells. In the present study, analysis of TRBV4 expansion in C57BL/6, DBA/2, B6D2 F1 mice, BXD recombinant inbred strains, and the progeny of C57BL/6×DBA/2 F1 hybrids backcrossed to C57BL/6 demonstrated strong cumulative dominance of the low DBA/2 trait and moderately high heritability (h ²~0.5). Two quantitative trait loci (QTLs) strongly associated with variance in TRBV4 expansion were identified using simple and composite mapping procedures. The first QTL is located on Chromosome (Chr) 17, near or proximal to H2. The second QTL is located on Chr 6 in a region spanning the Tcrb and Cd8a loci.