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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1086-1094.
Prepublished online as a Blood First Edition Paper on September 21, 2006; DOI 10.1182/blood-2006-03-011643.
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Submitted March 22, 2006
Accepted September 12, 2006
Early acquisition of cytolytic function and transcriptional changes in a primary CD8+ T-cell response in vivo
Christopher Chiu*, Adrian G Heaps, Vincenzo Cerundolo, Andrew J McMichael, Charles R Bangham, and Margaret FC Callan
Department of Immunology, Wright-Fleming Institute, Imperial College, London, UK
Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK
Division of Medicine, Department of Rheumatology, Imperial College, London, UK
* Corresponding author; email: c.chiu{at}imperial.ac.uk.
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 CTLs was analysed using Affymetrix 430 2.0 GeneChips and quantitative PCR. We demonstrated an early transcriptional burst with the greatest number of genes reaching peak expression 12 hours post-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.
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