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Department of Medicine, University of Cambridge, Cambridge, United Kingdom
Human CMV (HCMV) infection provides an informative model of how long term human CD8+ T cell memory is maintained in the presence of Ag. To clarify the phenotypic identity of Ag-experienced human CD8+ T cells in vivo, we determined the expression of costimulation and chemokine receptors on Ag-specific CD8+ T cells by quantifying individual virus-specific clones in different cell populations using TCR clonotypic probing. In healthy HCMV carriers, expanded CD8+ clones specific for either HCMV tegument protein pp65 or immediate-early protein IE72 are found in both CD45ROhigh cells and the subpopulation of CD45RAhigh cells that lack the costimulatory molecule CD28. In contrast to previous suggested models of CD8+ T cell memory, we found that in healthy virus carriers highly purified CD28-CD45RAhighCCR7- cells are not terminally differentiated, because following stimulation in vitro with specific HCMV peptide these cells underwent sustained clonal proliferation, up-regulated CD45RO and CCR5, and showed strong peptide-specific cytotoxic activity. In an individual with acute primary HCMV infection, HCMV pp65-specific CD8+ T cells are predominantly CD28-CD45ROhighCCR7-. During convalescence, an increasing proportion of pp65-specific CD8+ T cells were CD28-CD45RAhighCCR7-. We conclude that naive human CD8+ T cells are CD28+CD45RAhigh, express CCR7 but not CCR6, and are predominantly CD27+ and L-selectin CD62 ligand-positive. The phenotype CD27+CD45RAhigh should not be used to identify naive human CD8+ T cells, because CD27+CD45RAhigh cells also contain a significant subpopulation of CD28-CD27+ Ag-experienced expanded clones. Thus CD8+ T cell memory to HCMV is maintained by cells of expanded HCMV-specific clones that show heterogeneity of activation state and costimulation molecular expression within both CD45ROhigh and CD28-CD45RAhigh T cell pools.
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M. K. Gandhi, M. R. Wills, G. Okecha, E. K. Day, R. Hicks, R. E. Marcus, J. G. P. Sissons, and A. J. Carmichael Late diversification in the clonal composition of human cytomegalovirus-specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation Blood, November 1, 2003; 102(9): 3427 - 3438. [Abstract] [Full Text] [PDF]
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K. Rezvani, M. Grube, J. M. Brenchley, G. Sconocchia, H. Fujiwara, D. A. Price, E. Gostick, K. Yamada, J. Melenhorst, R. Childs, et al. Functional leukemia-associated antigen-specific memory CD8+ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem cell transplantation Blood, October 15, 2003; 102(8): 2892 - 2900. [Abstract] [Full Text] [PDF]
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 P.-M. Roger, J. Durant, M. Ticchioni, P. Halfon, J.-P. Breittmayer, C. Brignone, S. Chaillou, B. Dunais, P. Dellamonica, A. Bernard, et al. Apoptosis and proliferation kinetics of T cells in patients having experienced antiretroviral treatment interruptions J. Antimicrob. Chemother., August 1, 2003; 52(2): 269 - 275. [Abstract] [Full Text] [PDF]
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G. Strauss, I. Knape, I. Melzner, and K.-M. Debatin Constitutive Caspase Activation and Impaired Death-Inducing Signaling Complex Formation in CD95-Resistant, Long-Term Activated, Antigen-Specific T Cells J. Immunol., August 1, 2003; 171(3): 1172 - 1182. [Abstract] [Full Text] [PDF]
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