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.