Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells.
Following an infection or immunization, a primary CD8+ T cell response generally rises then falls rapidly before giving rise to a "memory" response. When we immunized mice with recombinant viral immunogens optimized to enhance the lytic capability of CD8+ T cells, we measured a profound depression in Ag-specific effector function after early restimulation. Indeed, a "mirror image" cytolytic capability was observed: the most powerful immunogens, as measured by cytolytic capacity 6 days after immunization, elicited the weakest secondary immune response when evaluated following an additional 6 days after restimulation. To understand the mechanism of this suppression, we examined the fate of splenocytes immunized with a vaccinia virus encoding Ag and IL-2 then restimulated ex vivo. We found that these splenocytes underwent an apoptotic cell death, upon early restimulation, that was not dependent on the engagement of the FasR (CD95). Unlike previously described mechanisms of "propriocidal cell death" and "clonal exhaustion," the cell death we observed was not an inherent property of the CD8+ T cells but rather was due to a population of splenocytes that stained positive for both the Mac-1 and Gr-1 surface markers. Deletion of these cells in vitro or in vivo completely abrogated the observed suppression of cytolytic reactivity of Ag-specific CD8+ T cells. These observations could account for the apparent absence of Ag-specific immune responses after some current vaccination regimens employing powerful immunogens. Finally, our results may shed new light on a mechanism for the suppression of CD8+ T cell responses and its effect on vaccine efficacy and on immune memory.
Bronte
V
V
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. vbronte@ux1.unipd.it
Wang
M
M
Overwijk
W W
WW
Surman
D R
DR
Pericle
F
F
Rosenberg
S A
SA
Restifo
N P
NP
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007108:Immune Tolerance; D007114:Immunization; D007117:Immunization, Secondary; D007376:Interleukin-2 / Q000235:genetics; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D016177:Macrophage-1 Antigen / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D001616:beta-Galactosidase / Q000235:genetics
D019496:Cancer Vaccines; D007376:Interleukin-2; D016177:Macrophage-1 Antigen; D001616:beta-Galactosidase