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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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