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Functional studies show that programming of CD8+T cells occurs early after initial antigen encounter within as little as 2 hours. To define the molecular basis of these events, we transferred TCR transgenic T cells from F5 Rag−/−mice into naive recipients and stimulated them with recombinant vaccinia expressing the immunodominant influenza epitope NP366-374. Transcription in epitope-specific cytotoxic T lymphocytes (CTLs) was analyzed using Affymetrix 430 2.0 GeneChips and quantitative polymerase chain reaction (PCR). We demonstrated an early transcriptional burst with the greatest number of genes reaching peak expression 12 hours after stimulation. Using in vivo cytotoxicity assays we demonstrated that early up-regulation of cytolytic genes was accompanied by acquisition of killing capacity within 24 hours of stimulation. However, T-cell proliferation was not observed until 48 hours. We therefore conclude that clonal expansion rather than acquisition of effector function is the rate-limiting step in the development of a primary CTL response.

The dynamics of human T-lymphotropic virus type-1 (HTLV-1) provirus expression in vivo are unknown. There is much evidence to suggest that HTLV-1 gene expression is restricted: this restricted gene expression may contribute to HTLV-1 persistence by limiting the ability of the HTLV-1–specific CD8+cell immune response to clear infected cells. In this study, we tested the hypothesis that derepression of HTLV-1 gene expression would allow an increase in CD8+cell–mediated lysis of HTLV-1–infected cells. Using histone deacetylase enzyme inhibitors (HDIs) to hyperacetylate histones and increase HTLV-1 gene expression, we found that HDIs doubled Tax expression in naturally infected lymphocytes after overnight culture. However, the rate of CD8+cell–mediated lysis of Tax-expressing cells ex vivo was halved. HDIs appeared to inhibit the CD8+cell–mediated lytic process itself, indicating a role for the microtubule-associated HDAC6 enzyme. These observations indicate that HDIs may reduce the efficiency of cytotoxic T-cell (CTL) surveillance of HTLV-1 in vivo. The impact of HDIs on HTLV-1 proviral load in vivo cannot be accurately predicted because of the widespread effects of these drugs on cellular processes; we therefore recommend caution in the use of HDIs in nonmalignant cases of HTLV-1 infection.