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-4hi). 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-4hi subset, whereas the frequency was low for other lymphocyte subsets studied (CD4+, CD8+VLA-4lo and B cells). In addition, numbers of CD8+VLA-4hi) cells constitute approximately 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-4hi 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.