Differential costimulation through CD137 (4–1BB) restores proliferation of human virus-specific “effector memory” (CD28− CD45RAHI) CD8+ T cells

• Published in: Blood Vol. 110; no. 13; pp. 4360 - 4366
• Main Authors: Waller, Edward C.P., McKinney, Nicola, Hicks, Ray, Carmichael, Andrew J., Sissons, J. G. Patrick, Wills, Mark R.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-12-2007; The Americain Society of Hematology
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Human viral diseases; Infectious diseases; Medical sciences; Microbiology; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Virology; Human; Cell proliferation; Effectory cell; Immune response; Herpesviridae; Cellular immunity; Betaherpesvirinae; Human cytomegalovirus; Memory lymphocyte; Infection; Virus; Antigen presenting cell; Costimulation; Viral disease; CD8 T lymphocyte
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-07-104604

In healthy carriers of human cytomegalovirus (HCMV), the virus-specific memory CD8+ T-cell population is often dominated by CD28− CD45RAhi 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− CD45RAhi 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+ CD45ROhi cells or CD28− CD45ROhi 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− CD45RAhi CD8+ T cells and not CD80, CD86, or CD275 (ICOSL). Therefore, CD28− CD45RAhi CD8+ T cells were not terminally differentiated but required a specific costimulatory signal for proliferation.