Submitted July 31, 2007
Accepted September 15, 2007
Differential co-stimulation through CD137 (4-1BB) restores proliferation of human virus-specific "effector memory" (CD28-CD45RAhi) CD8+ T Cells
Edward CP Waller, Nicola McKinney, Ray Hicks, Andrew J Carmichael, J.G. Patrick Sissons, and Mark R Wills*
Department of Medicine, University of Cambridge Clinical School, Cambridge, United Kingdom
* Corresponding author; email: mrw1004{at}cam.ac.uk.
In healthy carriers of human cytomegalovirus (HCMV), the virus-specific memory CD8+ T cell population is often dominated by CD28- CD45RAhi cells which 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- CD45RAhi CD8+ T cells are stimulated with viral peptide presented by autologous monocytes, the virus-specific T cells show early upregulation of CD137 (4-1BB) and CD278 (ICOS), re-express CD28, and proliferate with similarly high cloning efficiency in limiting dilution analysis as CD28+ CD45ROhi cells or CD28- CD45ROhi cells. Using peptide-pulsed autologous fibroblasts transfected with individual costimulatory ligands as antigen presenting cells, we show that CD137L is a key costimulatory ligand for proliferation of CD28- CD45RAhi CD8+ T cells and not CD80, CD86 or CD275 (ICOSL). Therefore CD28- CD45RAhi CD8+ T cells are not terminally differentiated but require a specific co-stimulatory signal for proliferation.
