Immune Recognition and Evasion: Molecular Aspects of Host–Parasite Interaction

298 Pages·1990·7.405 MB·English

by  L.H.T. Van Der Ploeg (Eds.)

IMMUNE RECOGNITION AND EVASION:
MOLECULAR ASPECTS OF
HOST-PARASITE INTERACTION
Edited by
LEX H. T. VAN DER PLOEG
CHARLES R. CANTOR
HENRY J. VOGEL
College of Physicians and Surgeons
Columbia University
New York, New York
ACADEMIC PRESS, INC.
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Library of Congress Cataloging-in-Publication Data
Immune recognition and evasion : molecular aspects of host-parasite
interaction / edited by Lex H.T. Van der Ploeg, Charles R. Cantor,
Henry J. Vogel,
p. cm.
Includes bibliographical references.
ISBN 0-12-711710-5 (alk. paper)
1. Immune recognition. 2. Host-parasite relationships-
-Immunological aspects. 3. Protozoan diseases—Immunological
aspects. I. Van der Ploeg, Lex H. T. II. Cantor, Charles R.,
Date. III. Vogel, Henry J. (Henry James), Date.
[DNLM: 1. Host-Parasite Relations. 2. Immunity, Cellular. QW
568 13146]
QR185.95.I47 1990
616.07'9-dc20
DNLM/DLC
for Library of Congress 90-102
CIP
Printed in the United States of America
90 91 92 93 9 8 7 6 5 4 3 2 1
Preface
Studies of parasite biology, focusing on the invasion of multicellular orga-
nisms by bacterial, protozoal, fungal, viral, or helminth parasites, have re-
vealed the intricacy of the genetic programs that control host-parasite
interactions. Analyses of the genetic basis of immune recognition, together
with insights into the limitations of the host's capacity to eliminate parasitic
infections, have furthered our understanding of immune recognition and
function. Investigations of parasite antigens and the mechanisms by which
parasites evade immune recognition have in turn revealed genetic and bio-
chemical mechanisms that parallel the immune control in complexity and
flexibility. The parasite s potential to scavenge nutrients and to utilize its
host's hormonal and genetic regulation, for the benefit of its own growth and
development, adds a new level of complexity to host-parasite interactions.
This complexity implies that our success in the elimination of some of these
devastating infectious diseases is dependent on research that addresses the
molecular basis of host-parasite interactions from a wide range of biological
disciplines. In this context, this volume discusses recent advances in the
determination of the structure of antigenic epitopes, the molecular mecha-
nisms of immune recognition and evasion, the action of cytokines and hor-
mones in host-parasite interactions, and the genetics of parasites.
It is a pleasure to acknowledge the advice and help of Dr. Frederick W.
Alt, Dr. George A. M. Cross, Dr. Harold S. Ginsberg, Dr. Victor Nussen-
zweig, Dr. Frederik R. Opperdoes, Dr. Samuel C. Silverstein, Dr. Jack L.
Strominger, Dr. Kenneth Stuart, and Dr. C. C. Wang.
We are grateful for the fine support of the College of Physicians and
Surgeons (P&S) of Columbia University without which this volume would
not have reached fruition. This volume was developed from a P&S Bio-
medical Sciences Symposium held at Arden House, on the Harriman Cam-
pus of Columbia University, from June 3 through June 5, 1988.
Lex H. T. Van der Ploeg
Charles R. Cantor*
Henry J. Vogel
* Present address: Human Genetics Center, Lawrence Berkeley Laboratory, University of California,
Berkeley, California 94720.
xiii
1
Genomic Organization of
the Τ Cell Receptor
AGNES CHAN AND ΤΑΚ W. MAK
The Ontario Cancer Institute
Departments of Medical Biophysics and Immunology
University of Toronto
Toronto, Canada M4X 1K9
INTRODUCTION
Two major cell types, namely the Τ and Β lymphocytes, have been shown
to be responsible for the regulation of the immune system. The Β lympho-
cytes recognize antigens by means of surface receptors known as the immu-
noglobulin molecules. These molecules are found to be encoded by noncon-
tiguous genes composed of the variable (V), diversity (D), joining (J), and
constant (C) segments. The availability of large numbers of V, D, and J gene
segments, frequent imprecise joining of the rearranged segments, and so-
matic mutation during Β cell replication provide diversity to these immu-
noglobulin molecules (for review, see Tonegawa, 1987).
Like immunoglobulins, the germline Τ receptor (TcR) genes are also com-
posed of noncontiguous V, D (in β and δ only), J, and C gene segments
(Takihara et al, 1988a, b; Toyonaga and Mak, 1987; Yanagi et al, 1984, 1985;
Sim et al, 1984; Hedrick et al, 1984; Chien et al, 1984). During Τ cell
ontogeny, these V, D, and J (or VJ) gene segments rearrange to form a
unique TcR gene encoding a functional variable domain, which is joined to
the C region sequences by RNA splicing following transcription. This pro-
cess of rearrangement is similar to that observed in the immunoglobulin loci
during Β cell development. The usage of different V, D, and J segments to
produce functional α or β chains is presumably random, proceeding by
positive or negative selection of effective Τ cells. On the other hand, de-
pending on the developmental stages or anatomical locations, there is a
preferential usage of the variable and constant 7 and δ chain genes (Ito et al,
1989; Groh et al, 1989; Asarnow et al, 1988; Takihara et al, 1990; Korman
3
Immune Recognition and Evasion: Copyright © 1990 by Academic Press, Inc.
Molecular Aspects of Host-Parasite Interaction All rights of reproduction in any form reserved.
4 AGNES CHAN AND ΤΑΚ W. MAK
et al., 1988; Loh et ah, 1988; Goodman and Lefrançois, 1988; Heilig and
Tonegawa, 1986). Like immunoglobulins, the TcR are diversified by somatic
recombination events, but unlike immunoglobulins, these receptor proteins
have not been shown to undergo further diversification by somatic mutation.
The protein structure of the two TcR heterodimers and their possible role
in antigen recognition have been subjected to extensive review in recent
literature (for reviews, see Brenner et al., 1988; Wilson et al., 1988; Caccia et
al, 1988a, b; Davis and Bjorkmann, 1988; Toyonagaand Mak, 1987; Kronen-
berg et al., 1986) and will not be discussed here. Instead, we will summarize
the recent findings on the genomic organization of the TcR genes.
GENOMIC ORGANIZATION OF THE
Τ CELL RECEPTOR GENES
THE a CHAIN GENES
The complete α chain locus is located on chromosome 14 in both man
(Caccia et al., 1985) and mouse (Dembic et al., 1985). The variable domain of
the α chain is encoded by only two gene segments (V and J) (Yanagi et al.,
1985). The V gene segments are composed of two exons separated by an
intron of 90 to 400 base pairs (bp). The first exon codes for the signal peptide
and the second exon codes for the last five residues of the signal peptide and
for the first 100 amino acids of the variable domain of the α chain (Yoshikai et
al., 1985, 1986). Analysis of human V genes from a cDNA library derived
a
from the peripheral lymphocytes suggested that there are about 40-50 V
a
gene segments in the α chain locus (Yoshikai et al., 1986). However, since the
usage of these different V gene segments is not random, the above statis-
a
tical estimates are probably lower than the actual available number of V
a
gene segments. Based on nucleotide sequences and Southern blot hybridiza-
tions, these V gene segments can be grouped into 22 subfamilies, half of
a
which contain a single member on the classification basis of homology great-
er than 75% at the nucleotide level (Wilson et al, 1988; Klein et al, 1988).
The number of variable region gene segments in mouse is estimated to be
about 100 (Arden et al., 1985; Chou et al., 1986). Based on Southern blot
hybridization analysis, these V gene segments can be grouped into 13-20
a
subfamilies. All of these subfamilies have multiple members, ranging from 2
to 10 (Arden et al, 1985).
The genomic organization of the human V gene segments was recently
a
determined using pulsed-field gel electrophoresis (Griesser et al., 1988).
Using 16 V probes derived from cDNAs encoding the different subfamilies,
a
the locations of these genes are mapped with respect to each other. The five
1. GENOMIC ORGANIZATION OF THE Τ CELL RECEPTOR 5
rare restriction enzymes used are Mlul, Sail, Sfil, Clal, and Xhol. Half of
the V gene subfamilies are found to locate on a 230-kb Sfil fragment. The
a
relative positions of each of these V gene segments are shown in Fig. 1. It is
a
worth noting that at least two pairs of members of the V subfamilies,
a
namely V 3/V ll and V 4/V 5, can be found together at different locations
a a a a
of the V locus as far as 600 kilobases (kb) apart. This observation supports
a
the current view that gene duplication was a common mode of increasing the
V gene diversity during evolution. In mouse, deletion mapping and pulsed-
a
field gel electrophoresis analysis have shown that members of the different
V subfamilies are interspersed across the V locus with the V region oc-
a a
cupying more than 100 kb (Wilson et al., 1988).
The J gene segments, located centromeric to the V region, are dis-
a a
persed over an area of at least 50 kb in man and 70 kb in mouse (Hayday et
al., 1985a; Winoto et al., 1985; Yoshikai et al., 1985). Each of the ] genes are
OL
separated on average by 1 kb (Hayday et al., 1985b), with the first J located
a
about 4 kb upstream to the single constant region (C ) (Hayday et al., 1985a;
a
Winoto et al., 1985). Unlike the V , ] gene segment usage appears to be
a OL
random. From the distribution of J gene usage in α chain cDNA clones,
a
statistical calculation indicates that there may be more than 100 J gene
a
Xho
Sfi
Xho. Xho Sfi SfiSfi f Xho Mlu y Cla
Sal Cla Mlu] Sfi Xho Sal Cl Y Xho | Sal | [ Cla Xho | Sal
CENTROMER TELOMER
h i.l. • • • , ' 1 Λ ' ν¥
î t f t f f t t(Xί^ Ca
4,5,6 19 Jo
3,11,14 1.1,3,7.1 I 1.2,4,5,3,11,2
8.1,12,4,5 I 7.2,8.2,10,12,13
Va Families 1.2,7.2,8.2 6,14,16
2,9
640 220 Mlu I
480 350 290 Sal I
420 270 190 Cla I
360 125 80 230 2 .5 Sfi
—IH
145 250 80 130 190 Xhol
H 1
I 1
lOOkb
Fig. 1. Marco restriction map of the human Τ cell receptor a chain locus (adapted from
Griesser et al., 1988). Fragments obtained with each enzyme are illustrated to scale below the
subregions with which hybridization has been demonstrated (arrows).
6 AGNES CHAN AND ΤΑΚ W. MAK
segments in the human α chain locus (Barth et al., 1985; Toyonaga and Mak,
1987), although only 46 J gene segments has been identified by nucleotide
a
sequence analysis so far (Yoshikai et al., 1985, 1986; Klein et al., 1988). The
J gene segments are very highly variable at the nucleotide level, with an
a
average nucleotide identity ranging from 40 to 60% (Klein et al., 1988).
Hence, the ] gene segments have not been grouped into subfamilies. In the
OL
murine α chain locus, 32 ] gene segments have been sequenced (Arden et
OL
al., 1985). Of those sequenced, most of them are encoded by distinct gene
segments, hence the repertoire of J gene segments is much greater than 30.
a
D region coding sequences have not been identified in the α chain. How-
ever, examination of cDNA clones sequences reveals the presence of addi-
tional nucleotides at the junctional region not encoded in the germline
genome (Klein et al., 1988). These nucleotides are thought to be the result of
Ν region diversification (Alt et al., 1984; Klein et al., 1988).
One constant region gene is found in the α chain locus. The gene segment
is composed of four exons. The first exon encodes the extracellular constant
domain and the second exon encodes the extracellular domain hingelike
region. The third exon encodes the transmembrane and cytoplasmic regions
while the fourth exon encodes only the 3' untranslated region (Hayday et al.,
1985b).
Recombination signals, similar to those of the immunoglobulin, are also
present in both human and mouse α chain locus. They are found flanking the
α chain segments, with long spacers 3' to the V genes and short ones 5' to
a
the J gene segments (Hayday et al., 1985a; Winoto et al., 1985; Yoshikai et
a
al, 1985).
THE β CHAIN GENES
The Τ cell receptor β chain locus is located on chromosome 7 in human
(Caccia et al., 1984; Isobe et al., 1988) and on chromosome 6 in mouse
(Caccia et al., 1984). The variable gene segments are composed of two exons.
The first exon codes for the signal peptide which is about 50 nucleotides
long, and the second exon codes for the last 5 residues of the signal peptide
and for the majority of the variable domain (Siu et al., 1984). Both cysteines
involved in the intradomain disulfide linkage are encoded by the V gene
ß
segments. Nucleotide sequences and Southern blot hybridizations have esti-
mated that there are at least 20 V chain gene segments in mouse (Barth et
ß
al., 1985; Behlke et al., 1985) and more than 60 V gene segments in human
ß
(Concannon et al., 1986; Kimura et al., 1986). Based on DNA sequence
analysis and Southern blot hybridization studies, these V gene segments
p
can be grouped into 17 and 20 subfamilies, respectively. Thirteen of the
human V subfamilies are found to consist of a single member each. In
ß
1. GENOMIC ORGANIZATION OF THE Τ CELL RECEPTOR 7
mouse, the single-member families are 17 in number (Wilson et al., 1988).
By using pulsed-field electrophoresis, chromosomal walking, and cosmid
and phage clonings, the locations of both the human and murine V gene
ß
segments have been determined (Fig. 2) (Wilson et al., 1988; Lee et al.,
1987; Lai et al, 1987, 1988; Lindsten et al, 1987; Chou et al, 1986). In
human, the V gene segments and the two Dß-Jß-Cß clusters are found on
ß
a S fil fragment spanning approximately 600 kb. All 40 V gene segments
ß
identified are mapped to the 5' end of the two D -J -C clusters (Lai et al.,
ß ß ß
1988). In mouse, 20 of the 22 known V gene segments are located on a 300-
ß
kb DNA fragment. All of the V gene segments, except V 14, are located
ß ß
upstream of the C regions. A functional murine Τ cell clone has been found
ß
to have a V 14 gene segment located 10 kb 3' to C 2 in a reverse transcrip-
ß ß
tional orientation (Malissen et al, 1986). Two three-member V subfamilies,
ß
V 5/8, are found to be together at different locations in the murine V locus
ß ß
(Wilson et al, 1988).
Downstream to the V genes are the diversity (D ) and joining (J ) gene
ß ß ß
segments. The cluster of D gene segments consisting of approximately 600
ß
nucleotides is 5' to the cluster of J region sequences, which is 2 to 5 kb 5' to
ß
the constant (C ) regions (Clark et al., 1984; Siu et al., 1984; Toyonaga et al.,
ß
1985).
Two constant region genes are found in the β chain locus for both human
and mouse. The coding sequences of the two C genes, C l and C 2, are
ß ß ß
highly homologous with only six amino acid differences in humans and four
amino acid differences in mice (Toyonaga et al, 1985; Caccia et al, 1988a).
The C gene is divided into four exons, with the first two exons encoding
ß
most of the extracellular constant domain. The third exon encodes the major-
ity of the transmembrane protein region, while the fourth exon encodes the
cytoplasmic coding sequences and the 3' untranslated region (Caccia et al,
1988b).
13
13
7 4 [Z_lj]l4 iß**. 65
' L "ο J
3.2 3.1 7 17
Β.
Fig. 2. Physical map of the Τ cell receptor β chain locus in (A) human and in (B) mouse
(adapted from Lai et al, 1987, 1988; Wilson et al, 1988; Chou et al, 1977; Lee et al, 1987;
Malissen et al, 1986). Horizontal arrows above each gene segment indicate its transcriptional
orientation. Pseudo-Vß genes are marked with an asterisk.
8 AGNES CHAN AND ΤΑΚ W. MAK
Recombinational signals, similar to those of the immunoglobulin, are also
found flanking the V , D , and J genes (Clark et al, 1984; Malissen et al.,
ß ß ß
1986; Kavaler et al, 1984; Siu et al, 1984).
THE 7 CHAIN GENES
The Τ cell receptor 7 chain locus is located on chromosome 13 in mouse
(Kranz et al, 1985) and on the short arm of chromosome 7 in human (Murre
et al., 1985). The organization of the murine 7 gene locus is quite distinct
from either the α or β chains (Fig. 3). Analysis of the genomic organization of
the 7 chain genes in BALB/c and BIO mice reveals three cross-hybridizing
constant regions (C 1, C 2, C 3) and a unique Cyl constant region (Born et
7 7 7
al, 1986; Hayday et al, 1985a; Iwamoto et al, 1986; Saitoh al, 1984). Each
C segment is composed of three exons. The first exon encodes the extra-
7
cellular constant domain and the second exon encodes the connector pep-
tide, while the third exon encodes the transmembrane cytoplasmic se-
quences (Hayday et al, 1985a; Garman et al, 1986). Although C l, C 2, and
y 7
C 3 gene segments are highly homologous, there are important differences
7
between them. In BALB/c mice, C 1 has one potential N-glycosylation site,
7
while C 2 has none, but both code for functional proteins, and C 3 is a
7 7
pseudogene. Each of the C genes, except C 1, is associated with its own V
7 7
and J gene segments. C 1 has been found to associate with four V segments
7
and one J segment (Garman et al., 1986; Heilig and Tonegawa, 1986; Trau-
B
C/4 J/4 V/ J/2 C/2 C/3 J/3 V/3 Cyl Jyl Vy
3 4 2 5
V/-
v Ψ 1
Fig. 3. Schematic diagram of the genomic (A) human and (B) murine 7 chain locus (adapted
from Brenner et al., 1988). (A) Nomenclature of the human 7 chain locus is according to
Quertermous et al. (1987) and Strauss et al. (1987). There are four subfamilies of W y gene
segments. The largest subfamily is V 71, which consists of nine closely related members; how-
ever, four of them are pseudogenes, as indicated with a ψ. (Β) Nomenclature of the murine 7
chain locus as according to Garman et al. (1986). Parentheses surrounding ν γ3-1Ύ3-0Ύ3 indi-
cated that the orientation of this cluster relative to other clusters is unknown.
1. GENOMIC ORGANIZATION OF THE Τ CELL RECEPTOR 9
necker et al, 1986; Pelkonen et al, 1987). Similar to the α and β chain
genes, the murine V gene segments are also composed of two exons. The
7
first exon codes for the signal peptide and the second exon codes for the
majority of the variable domain of the 7 chain (Hayday et al., 1985a). Using
the nomenclature of Garman et al. (1986), five V subfamilies have been
7
defined. Four of the subfamilies contain only one member each, with the
exception of V 1, which consists of three members. Members within the V 1
7 7
subfamily displayed up to 88% homology at the amino acid level (Hayday et
al., 1985a). The usage of V genes in the adult thymic population is nonran-
7
dom, with most cells expressing the product of a single rearranged gene, V
7
2J 1C 1 (Pardoll et al, 1987). On the other hand, V 3 is preferentially used
7 7 7
in fetal thymocytes (Ito et al., 1989; Heilig and Tonegawa, 1986). There are
four J regions in the murine 7 locus, each associated with its own C region.
At the amino acid level, J and J 2 are identical, whereas J 4 differs from
7 7 7
them at 50% of the residues (Hayday et al, 1985b; Iwamoto et al, 1986).
The genomic organization of the human 7 genes is similar to that of
murine and human β chain genes. The 7 locus spans roughly 160 kb (Strauss
et al, 1987), consisting of at least 14 V segments, 5 J segments, and 2 C
segments (LeFranc and Rabbits, 1985; Murre et al, 1985; Quertermous et
al, 1987; LeFranc et al, 1986; Dialynas et al, 1986; Forster et al, 1987;
Huck and LeFranc, 1987; Huck et al, 1988) (Fig. 3). The V gene segments
7
can be divided into four subfamilies (LeFranc et al, 1986; Yoshikai et al,
1987). Most of the subfamilies consist of one member each. The largest
subfamily is VI, which consists of nine closely related members; however,
only five are able to encode functional peptides (Strauss et al., 1987; Forster
et al., 1987). Comparisons among V sequences reveal 76-91% homology at
the amino acid level among members of this subfamily (LeFranc et al,
1986c; Brenner et al, 1988). Homology between subfamilies, however, is
only about 20 to 40% (LeFranc et al., 1986; Forster et al., 1987; Huck et al.,
1988). Like the TcRß chain, the V segment is encoded in two exons, a
7
hydrophobic leader segment and a variable region. At least five joining (J)
segments have been identified in the human 7 locus (LeFranc et al, 1986;
Quertermous et al, 1986; Huck and LeFranc, 1987; Tighe et al, 1987).
These segments can be divided into two groups, with J 1.1, J 12, and J 1.3
7 7 7
located upstream of C 1, and J 2.1 and J 2.3 located upstream of C 2, J 1.3
7 7 7 7 7
and J 2.3 are identical to each other at the amino acid level, differing by only
7
a single nucleotide, whereas J 1.1 and J 2.1 share roughly 70% homology
7 7
with each other at the amino acid level. J 1.2 does not have a counterpart
7
that associates with C 2, and J 1.1, 1.2, and 1.3 share about 50% homology
7 7
with each other at the amino acid level (Brenner et al., 1988). Two constant
regions are found in the human 7 chain locus. Both C genes have a struc-
7
ture similar to that of the C and C genes, with an extracellular constant
a p