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Journal of Virology, September 1998, p. 7440-7449, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

CD40 Ligand-Mediated Interactions Are Involved in the Generation of Memory CD8+ Cytotoxic T Lymphocytes (CTL) but Are Not Required for the Maintenance of CTL Memory following Virus Infection

Persephone Borrow,1,* David F. Tough,2 Danelle Eto,1 Antoinette Tishon,1 Iqbal S. Grewal,3 Jonathan Sprent,2 Richard A. Flavell,3 and Michael B. A. Oldstone1

Division of Virology, Department of Neuropharmacology,1 and Department of Immunology,2 The Scripps Research Institute, La Jolla, California 92037, and Section of Immunobiology, Howard Hughes Medical Institute Research Laboratories, Yale University School of Medicine, New Haven, Connecticut 065103

Received 22 April 1998/Accepted 17 June 1998

CD8+ cytotoxic T lymphocytes (CTL) play a key role in the control of many virus infections, and the need for vaccines to elicit strong CD8+ T-cell responses in order to provide optimal protection in such infections is increasingly apparent. However, the mechanisms involved in the induction and maintenance of CD8+ CTL memory are currently poorly understood. In this study, we investigated the involvement of CD40 ligand (CD40L)-mediated interactions in these processes by analyzing the memory CTL response of CD40L-deficient mice following infection with lymphocytic choriomeningitis virus (LCMV). The maintenance of memory CD8+ CTL precursors (CTLp) at stable frequencies over time was not impaired in CD40L-deficient mice. By contrast, the initial generation of memory CTLp was affected. CD40L-deficient mice produced lower levels of CD8+ CTLp during the primary immune response to LCMV than did wild-type controls, despite the fact that the LCMV-specific effector CTL response of CD40L-deficient mice was indistinguishable from that of control animals. The differentiation of naïve CD8+ T cells into effector and memory CTL thus involves pathways that can be discriminated from each other by their requirement for CD40L-mediated interactions. Expression of CD40L by CTLp themselves was not an essential step during their expansion and differentiation from naïve CD8+ cells into memory CTLp; instead, the reduction in memory CTLp generation in CD40L-deficient mice was likely a consequence of defects in the CD4+ T-cell response mounted by these animals. These results thus suggest a previously unappreciated role for CD40L in the generation of CD8+ memory CTLp, the probable nature of which is discussed.

* Corresponding author. Present address: The Edward Jenner Institute for Vaccine Research, Compton, Newbury, Berkshire RG20 7NN, United Kingdom. Phone: 1635 577913. Fax: 1635 577901. E-mail: seph.borrow{at}bbsrc.ac.uk.

Journal of Virology, September 1998, p. 7440-7449, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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