Differential costimulation through CD137 (4-1BB) restores proliferation of human virus-specific "effector memory" (CD28(-) CD45RA(HI)) 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: United States 15.12.2007
• Subjects: Antigens, Differentiation, T-Lymphocyte; Antigens, Viral - immunology; CD28 Antigens; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Cells, Cultured; Cytomegalovirus; Fibroblasts - cytology; Humans; Immunologic Memory; Inducible T-Cell Co-Stimulator Protein; Leukocyte Common Antigens; Signal Transduction - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics; Up-Regulation
• ISSN: 0006-4971
• 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(-) 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.