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.
Christensen
J P
JP
Institute of Medical Microbiology, University of Copenhagen, Denmark.
Röpke
C
C
Thomsen
A R
AR
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002453:Cell Cycle / Q000276:immunology*; D003609:Dactinomycin / Q000031:analogs & derivatives; D005260:Female; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D039041:Integrin alpha4beta1; D016023:Integrins / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis*
D005456:Fluorescent Dyes; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D003609:Dactinomycin; C025942:7-aminoactinomycin D