Virus-induced polyclonal T cell activation is followed by apoptosis: Partitioning of CD8(+) T cells based on alpha 4 integrin expression

Systemic infection with lymphocytic choriomeningitis virus (LCMV) is accompanied by marked splenomegaly, primarily reflecting the accumulation of CD8(+) T cells with an activated phenotype (e.g. VLA-4(hi)). Analysis of DNA content using 7-aminoactinomycin-D revealed that as many as 30% of CD8(+) T cells are cycling around day 6 post-infection and that virtually all cycling cells express a high level of VLA-4. In accord with the relatively stable CD4(+) cell number, only few cycling CD4(+) cells were observed, Following virus control, splenic lymphocyte numbers decreased gradually and during this period many apoptotic cells were detected in the white pulp using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. Flow cytometric analysis of DNA content revealed a high frequency of cells with subnormal levels of DNA in the CD8(+)VLA-4(hi) subset, whereas the frequency was low for other lymphocyte subsets studied (CD4(+), CD8(+)VLA-4(lo) and a cells), In addition, numbers of CD8(+)VLA-4(hi) cells constitute similar to 30% of splenocytes at the peak of the response and undergo preferential decrease during normalization of splenocyte numbers, Together these findings indicate that LCMV-induced activation of T cells is followed by apoptosis of many of the activated cells, Those CD8(+)VLA-4(hi) cells which do persist in LCMV immune mice are more sensitive to treatment with the cell-cycle-specific drug hydroxyurea than are phenotypically naive T cells, Our results therefore indicate that LCMV infection induces polyclonal activation of CD8(+) cells which is followed by apoptosis of most of the triggered cells while a smaller subset persists as a primed population which include cycling cells.