Differential costimulation through CD137 (4-1BB) restores proliferation of human virus-specific "effector memory" (CD28(-) CD45RA(HI)) CD8(+) T cells.
In healthy carriers of human cytomegalovirus (HCMV), the virus-specific memory CD8(+) T-cell population is often dominated by CD28(-) CD45RA(hi) cells that exhibit direct ex vivo cytotoxicity but whose capacity for proliferation and generation of further memory cells has been questioned. We show that when highly purified CD28(-) CD45RA(hi) CD8(+) T cells are stimulated with viral peptide presented by autologous monocytes, the virus-specific T cells show early up-regulation of CD137 (4-1BB) and CD278 (ICOS), re-express CD28, and proliferate with similarly high cloning efficiency in limiting dilution analysis as CD28(+) CD45RO(hi) cells or CD28(-) CD45RO(hi) cells. Using peptide-pulsed autologous fibroblasts transfected with individual costimulatory ligands as antigen presenting cells, we showed CD137L to be a key costimulatory ligand for proliferation of CD28(-) CD45RA(hi) CD8(+) T cells and not CD80, CD86, or CD275 (ICOSL). Therefore, CD28(-) CD45RA(hi) CD8(+) T cells were not terminally differentiated but required a specific costimulatory signal for proliferation.
Waller
Edward C P
EC
Department of Medicine, University of Cambridge Clinical School, Cambridge, UK.
McKinney
Nicola
N
Hicks
Ray
R
Carmichael
Andrew J
AJ
Sissons
J G Patrick
JG
Wills
Mark R
MR
D000945:Antigens, Differentiation, T-Lymphocyte; D000956:Antigens, Viral / Q000276:immunology*; D018106:CD28 Antigens; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003587:Cytomegalovirus; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007156:Immunologic Memory; D060889:Inducible T-Cell Co-Stimulator Protein; D017493:Leukocyte Common Antigens; D015398:Signal Transduction / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics; D015854:Up-Regulation
D000945:Antigens, Differentiation, T-Lymphocyte; D000956:Antigens, Viral; D018106:CD28 Antigens; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D017493:Leukocyte Common Antigens