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Cell Cycle-Related Acquisition of Cytotoxic Mediators Defines the Progressive Differentiation to Effector Status for Virus-Specific CD8⁺ T Cells¹

Misty R. Jenkins^2,*, Justine Mintern^*, Nicole L. La Gruta^*, Katherine Kedzierska^*, Peter C. Doherty^*, and Stephen J. Turner^3,*

^* Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia; and Department of Immunology St. Jude Children’s Research Hospital, Memphis, TN 38105

Although analysis of virus-specific CTL function at the peak of infection suggests that granzyme (grz) and perforin (pfp) gene expression is not coregulated, early differentiation events leading to acquisition of function are poorly understood. Using a combination of CFSE dilutions and single-cell RT-PCR, effector gene expression was determined early after CTL activation. There were low levels of pfp and grz expression at division 3, with increased expression by divisions 6–8. The increase in effector mRNA expression with division correlated with increasing ex vivo cytotoxicity. Of the mRNA transcripts detected at division 3, there was an increased frequency of grzB and grzK (compared with grzA or pfp), and this pattern was also observed at later divisions. The prevalence of OT-I CTL expressing grz/pfp mRNA was equivalent for the divided CD62L^high and CD62L^low sets, but the concentrations of grzB protein, levels of CTL activity, and the absolute amounts of grzB transcript were substantially greater for the CD62L^low population. Thus, while effector gene expression can be acquired early, maturation of cytotoxic capacity requires extended differentiation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by an Australian Postgraduate Scholarship awarded to M.R.J.; an National Health and Medical Research Council Burnet Award and a Victorian Government Science, Technology and Innovation grant awarded to P.C.D.; an National Health and Medical Research Council R.D. Wright Fellowship awarded to K.K. and N.L.G.; a Pfizer Senior Research Fellowship awarded to S.J.T.; a University of Melbourne C.R. Fellowship awarded to J.M.; and a Melbourne University Early Career Researcher grant awarded to S.J.T. and J.M.

² Current address: University of Cambridge, Cambridge Institute for Medical Research, Wellcome/Medical Research Council Building, Hills Rd, Cambridge, CB2 0XY, United Kingdom.

³ Address correspondence and reprint requests to Dr. Stephen Turner, University of Melbourne, Department of Microbiology and Immunology, Parkville, Victoria, Australia 3010. E-mail address: sjturn{at}unimelb.edu.au

⁴ Abbreviations used in this paper: pfp, perforin; grz, granzyme; MLN, mediastinal lymph node; T_EM, T effector memory cell; T_CM, T central memory cell; i.n., intranasally.

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The JI 2008 181: 3729-3730. [Full Text]  

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