Cytotoxic T-Lymphocytes in Human Viral and Malaria Infections

215 Pages·1994·5.69 MB·English

by  Michael B. A. Oldstone (eds.)

Current Topics in
Microbiology
189 and Immunology
Editors
A. Capron, Lille . R.W. Compans, Atlanta/Georgia
M. Cooper, Birmingham/Alabama' H. Koprowski,
Philadelphia . I. McConnell, Edinburgh . F. Melchers, Basel
M. Oldstone, La Jolla/California . S. Olsnes, Oslo
M. Potter, Bethesda/Maryland . H. Saedler, Cologne
P.K. Vogt, Los Angeles' H. Wagner, Munich
I. Wilson, La Jolla/California
Cytotoxic T-Lymphocytes
in Human Viral and
Malaria Infections
Edited by M. B.A. Oldstone
With 13 Figures and 21 Tables
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
Budapest
Michael BA Oldstone
Department of Neuropharmacology
Division of Virology
The Scripps Research Institute
10666 North Torrey Pines Road
La Jolla, California 92037
USA
Cover illustration: See page 4, Fig. 1a .
Cover design: Harald Lopka, IIvesheim
ISSN 0070-217X
ISBN-13: 978-3-642-78532-0 e-ISBN-13: 978-3-642-78530-6
001: 10.1007/978-3-642-78530-6
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© Springer-Verlag Berlin Heidelberg 1994
Library of Congress Catalog Card Number 15-12910
Softcover reprint of the hardcover 15t edition 1994
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Contents
The Role of Cytotoxic T Lymphocytes in Infectious
Disease: History, Criteria, and State of the Art
M.BA OLDSTONE ............... .
Therapeutic Reconstitution of Human Viral
Immunity by Adoptive Transfer of Cytotoxic
T Lymphocyte Clones
S.R. RIDDELL and P.O. GREENBERG . . . . . . 9
Cytotoxic T Lymphocytes in Human
Immunodeficiency Virus Infection: Responses to
Structural Proteins
R.P. JOHNSON and B.D. WALKER ......... 35
Cytotoxic T Lymphocytes in Human
Immunodeficiency Virus Infection:
Regulator Genes
Y. RIVIERE, M.N. ROBERTSON, and F. BUSEYNE 65
Cytotoxic T Lymphocytes Specific for Influenza
Virus
A McMICHAEL ................ 75
Cytotoxic T Lymphocytes in Dengue Virus
Infection
I. KURANE and F.A ENNIS .......... 93
Cytotoxic T Cells in Paramyxovirus Infection of
Humans
S. DHIB-JALBUT and S. JACOBSON ..... 109
Cytotoxic T Cells and Human Herpes Virus
Infections
L.K. BORYSIEWICZ and J.G.P. SISSONS ... 123
Cytotoxic T Lymphocyte Responses Against
Measles Virus
F.G.C.M. UYTDEHAAG, R.S. VAN BINNENDIJK,
M.J.H. KENTER, and AD.M.E. OSTERHAUS. . 151
VI Contents
The Class I-Restricted Cytotoxic T Lymphocyte
Response to Predetermined Epitopes in the
Hepatitis Band C Viruses
A. CERNY, C. FERRARI, and F.V. CHISARI . . 169
Cytotoxic T Lymphocytes in Humans Exposed to
Plasmodium falciparum by Immunization or
Natural Exposure
S.L. HOFFMAN, M. SEDEGAH, and A. MALIK 187
Subject Index ................. 205
List of Contributors
(Their addresses can be found at the beginning of their
respective chapters.)
BORVSIEWICZ L.K. 123 MALIK A ....... 187
BUSEVNE F. 65 McMICHAEL A. .... 75
CERNV A .... 169 OLDSTONE M.B.A . . 1
CHISARI F.v. .. 169 OSTERHAUS AD.M.E. 151
DHIB-JALBUT S. 109 RIDDELL S.R. ...... 9
ENNIS FA ....... 93 RIVIERE Y. . ....... 65
FERRARI C. .... 169 ROBERTSON M.N. 65
GREENBERG P.o. 9 SEDEGAH M. 187
HOFFMAN S.L. 187 SISSONS J.G.P. o ••• 123
JACOBSON S. 109 UVTDEHAAG F.G.C.M. 151
JOHNSON R.P. 35 VAN BINNENDIJK R.S. 151
KENTER M.J.H. 151 WALKER B.D. ..... 35
KURANE I. ... 93
The Role of Cytotoxic T lymphocytes in
Infectious Disease: History, Criteria,
and State of the Art
M. B. A. OLDSTONE
Observations made on children with genetic deficiencies of their immune
system reveal that those lacking the capacity to make antibodies nevertheless
handle most viral infections as well as normal individuals do. Such a- or
hypogammaglobulinemic children are often susceptible to bacterial infec-
tions. Conversely, children with genetic deficiencies in their ability to mount
cell-mediated immune responses or those who acquire diseases of lymphoid
tissues later in life are often susceptible to a range of viral infections (reviewed
in GOOD 1991; RICHES 1992).
The immune system consists of humoral (antibody) and cellular (lym-
phocyte, monocyte, macrophage) responses that most often function syner-
gistically to offer the host protection from invading microbes. Immunization,
primarily developed and used most successfully against agents causing acute
infection in humans and domestic animals, has been focused toward raising
and enhancing antibody responses to glycoprotein or structural protein
antigens present on surface virions, although cytotoxic T lymphocytes (CTL)
also play major roles in the control of acute infection. Protection from
persistent infection is more complex. The viruses are cell associated and often
viral surface glycoprotein expression is downregulated (BUCHMEIER and
WELSH 1979; OLDSTONE and BUCHMEIER 1982; liPKIN et al. 1989). In this
scenario, to act against virus infected cells, antibodies are not efficient for
lysing infected cells. Several million antibody molecules are needed, along
with effector molecules of the complement system, to destroy virally infected
cells-an ineffective system (SISSONS et al. 1979,1980).
To better handle persistent infection, the organism's preference is to-
wards the other effector arm of the immune response, consisting of lym-
phocytes, which detect very low levels of viral antigen on surfaces of infected
cells. These lymphocytes are cytotoxic for virally infected cells. Indeed, T cells
and CTL by inference are believed to require no more than 100 viral protein
(peptide) molecules (DEMOTZ et al. 1990) for activation. CTL can recognize
viral sequences expressed on cells that antiviral antibodies are unable to
detect. CTL are effective against nonglycosylated immediate-early or early
proteins of a virus that are transcribed many hours before structural viral
Virallmmunobiology Laboratory, Division of Virology, Department of Neuropharmacology, The
Scripps Research Institute, La Jolla, CA 92037, USA
Current Topics in Microbiology and Immunology, Vol. 189
© Springer·Verlag Berlin' Heidelberg 1994
2 M. B. A. Oldstone
proteins are made and, most importantly, prior to assembly of the virus into an
infectious unit (reviewed in OLDSTONE 1991). Further, CTL recognize infect-
ed cells as foreign and destroy them during the latent period of virus infection
when the late-acting genes (that encode structural viral proteins) are
blocked. CTL can effectively and efficiently recognize and lyse a virally
infected cell expressing regulatory proteins (i.e., Nef of human immunodefi-
ciency virus, HIV, immediate-early gene product of cytomegalovirus, CMV)
and proteins of the replicative complex (i.e., nonstructural, nuclear protein of
influenza virus, Pol and Gag of H IV), all usually made early in the infectious
cycle. The strategic advantage to the host in its battle with viruses is that the
CTL effector arm can eliminate potential factories (cells) before they produce
a finished infectious product (ZINKERNAGEL and ALTHAGE 1977; OLDSTONE
1991) .
Now, in 1993, it is abundantly clear that virus-specific CTL are generated
in most, if not all, infections by human RNA and DNA viruses. This volume is
dedicated towards collecting and disseminating this information. However,
the role played in controlling human infection is often circumstantial unless it
occurs in genetically deficient or lymphoid-depleted individuals. Yet a pleth-
ora of experimental animal studies in which CTL are chemically or genetically
deleted combined with reconstitution studies with CTL clones attest to their
commanding role in the control of several viral infections, including those
with lymphocytic choriomeningitis virus (LCMV), influenza virus, respiratory
syncytial virus, CMV infections as well as an important role in rabies and
herpes simplex virus infections. Even in the LCMV model, which is acknow-
ledged to be controlled by CTL activity, antibodies can be shown to playa
role. For example, CTL reduce viral titers by 4-5 logs (BYRNE and OLDSTONE
1984) and antibodies by 1-2 logs (BALDRIDGE and BUCHMEIER 1992).
Interestingly, the murine model of CMV and human CMV point not only to
effectiveness of CTL, but a role for NK cells and antibody (BIRON et al. 1989;
KOSZINOWSKI et al. 1990). While focusing on CTL, it is nevertheless important
to remember the synergistic role of other participants in the immune response.
How do CTL work? CTL recognize proteolytic fragments of viral proteins
that are presented at the cell surface by major histocompatibility complex
(MHC) glycoprotein molecules (ZINKERNAGELand DOHERTY 1974; TOWNSEND
et al. 1986). MHC molecules are divided into class I and class II, with class I
molecules recognized by a CTL subset that bears the CD8 surface marker and
class II molecules recognized by CTL or T-helper cells that bear the CD4
surface marker. MHC class I utilizes primarily a cytosolic pathway. MHC class
I is found on nearly all cells in the body, an exception being neurons (JOLY
et al. 1991; JOLY and OLDSTONE 1992). CTL recognize viral peptides bound
to the M HC glycoprotein. The bound peptide sequence is linear and occurs as
a consequence of proteolytic fragmentation of a viral protein usually syn-
thesized within the cell. The number of peptides per viral protein able to
complex with a M HC glycoprotein in a manner that allows CTL recognition is
limited and ranges from one to generally no more than three peptides per viral
The Role of Cytotoxic T Lymphocytes in Infectious Disease 3
protein, although recent observations with H IV suggest a larger number of
epitopes per viral proteins for this~infection (WALKER and PLATA 1990). The
size of the peptide has been mapped experimentally and consists optimally of
nine to 12 amino acids (reviewed in OLDSTONE 1991 L although lower affinity
recognition with as few as five amino acids has been noted (WHITTON et al.
1989). Mapping of epitopes utilized recombinant technology, overlapping
peptides, and single amino acid truncations from the amino or carboxy
termini to initially decode the minimal and optimal peptide size required for
CTL recognition as well as recording functional lysis of target cells. Recently
the M HC-peptide complex has been directly isolated and chemically identi-
fied from virally infected cells (ROTZSCHKE et al. 1990; VAN BLEEK and
NATHANSON 1990).
There are a number of milestones in the tale of deciphering CTL activity and
structure. The first occurred in 1968, when Brunner and Cerottini, working in
Lausanne, Switzerland, reported the use of the quantitative chromium-51
release assay as a marker of membrane injury after cell-cell interaction
(BRUNNER et al. 1968). The utility of the assay to study lymphocyte-target
cell interactions was appreciated by Cerottini and his colleagues (reviewed in
CEROTTINI 1993). Shortly thereafter, Cerottini came as a postdoctoral fellow
to Scripps in La Jolla, and on his urging I tested and observed that lym-
phocytes from mice primed with LCMV lysed (51 Cr release) syngeneic
LCMV-infected murine targets, but not targets infected either with an indif-
ferent virus or target cells of monkey origin infected with LCMV (OLDSTONE
et al. 1969; OLDSTONE and DIXON 1971). Concurrently, Lundstedt in Mor-
gens Volkert's laboratory in Copenhagen, also working with LCMV, found
roughly equivalent results (LUNDSTEDT 1969). At this time Martin Raft in
Avrion Mitchinson's laboratory in London began utilizing antibody to Th1.2
to segregate T (thymus) -derived from B (bone marrow) -derived lym-
phocytes, and this reagent was then utilized by Cole, Nathanson, and
Pendergast in Baltimore to document that the killer lymphocytes in LCMV
mediating cell injury bore the Th1.2 marker (COLE et al. 1972). Next the
seminal observation by ZINKERNAGEL and DOHERTY (1974) in Canberra,
Australia, opened wide this field by documenting the requirement for MHC
restriction in CTL recognition of the target cell. This contribution also pointed
to a role for MHC transplantation antigens and suggested a selective advan-
tage to the host for M H C diversity. Thereafter, many laboratories docu-
mented and continue to show CTL killing with MHC restriction and virus
specificity for many viruses. In the late 1970s and early 1980s, Askonas (LIN
and ASKONAS 1981) in London and Braciale (LUKACHER et al. 1984) in St.
Louis, by obtaining and using CTL clones, allowed a more rigorous analysis
of CTL recognition and activity. Alain Townsend, Andrew McMichael, and
their colleagues provided the next advance when they reported that a peptide
from the protein and not the whole viral protein was bound to the MHC for
CTL recognition (TOWNSEND et al. 1986). Thereafter, Bevan in La Jolla show-
ed that microinjected cytoplasmic. peptide was presented to MHC (MOORE