MHC Ligands and Peptide Motifs

467 Pages·1997·14.74 MB·English

by  Hans-Georg Rammensee

Molecular Biology Intelligence Unit
Jutta Bachmann · Stefan Stevanovic
Hans-Georg Rammensee
MHC Ligands and
Peptide Motifs
MOLECULAR
BIOLOGY
INTELLIGENCE
UNIT
MHCLigands
and Peptide Motifs
Hans-Georg Rammensee
Jutta Bachmann
Stefan Stevanovic
University ofTiibingen
Tiibingen, Germany
Springer-Verlag
Berlin Heidelberg GmbH AUSTIN, TEXAS
U.S.A.
MOLECULAR BIOLOGY INTELLIGENCE UNIT
MHC Ligands and Peptide Motifs
LANDES BIOSCIENCE
Austin, Texas, U.S.A.
International Copyright © 1997 Springer-Verlag Berlin Heidelberg
Originally published by Springer-Verlag in 1997
Softcover reprint of the hardcover 1s t edition 1997
All rights reserved.
No part of this book may be reproduced or transmitted in any form or by any
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tion storage and retrieval system, without permission in writing from the publisher.
, Springer
International ISBN 978-3-662-22164-8
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Library of Congress Cataloging-in-Publication Data
Rammensee, Hans-Georg, 1953- .
MHC ligands and peptide motifs / Hans-Georg Rammensee, Jutta Bachmann,
Stefan Stevanovic
p. cm. - (Molecular biology intelligence unit)
Includes bibliographical references and index.
ISBN 978-3-662-22164-8 ISBN 978-3-662-22162-4 (eBook)
DOI 10.1007/978-3-662-22162-4
1. Major histocompatibility complex. I. Bachmann, Jutta, 1961- . II. StevanoviC,
Stefan, 1959- . III. Title. IV. Series.
[DNLM: 1. Major Histocompatibility Complex--physiology. WO 680 R174m
1997]
QRI84.315.R35 1997
616.07'9-dc21
DNLMIDLC
for Library of Congress 97-18997
CIP
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CONTENTS
1. History and Overview .................................................................. 1
History ......................................................................................... 1
Overview ...................................................................................... 4
Conclusion ................................................................................... 9
2. The MHC Genes ......................................................................... 17
Introduction .............................................................................. 17
HLA Class I Region ................................................................... 18
HLA Class II Region .................................................................. 21
HLA Class III Region ................................................................ 25
3. The Structure ............................................................................ 141
MHC Class I ............................................................................ 141
MHC Class II ........................................................................... 143
4. The Function ............................................................................ 217
Part I ......................................................................................... 217
Peptide Motifs ......................................................................... 217
MHC I Peptide Motifs, Part One: Length .............................. 218
MHC I Peptide Motifs, Part Two: Anchors ........................... 218
MHC I Peptide Motifs, Part Three: Auxiliary Anchors
and Preferred Residues ........................................................ 219
MHC I Peptide Motifs, Part Four: Unfavorable Residues .... 220
MHC II Peptide Motifs, Part One: Length ............................ 220
MHC II Peptide Motifs, Part Two: Anchors .......................... 221
Prediction Procedures ............................................................. 223
Building-Up Patterns .............................................................. 224
Prediction ofMHC II Restricted Epitopes ............................. 227
Part II ....................................................................................... 227
The 'Classical' MHC I Loading Pathway ............................... 228
MHC Class II Loading ............................................................ 231
5. Recognition by Immune Cells ................................................. 371
Natural Killer Cells .................................................................. 371
Antigen-Specific T Cells .......................................................... 372
Alloreactivity and Transplantation ........................................ 373
Tissue Specific Cytotoxic T -cells Produced by Subtractive
Immunization In Vitro (1984 Hans-Georg Rammensee) ... 375
Immunity Against Infection ................................................... 381
Autoimmunity and Self Tolerance ......................................... 382
Tumor Immunology ............................................................... 383
Appendix A: Useful Internet Addresses ................................ 449
Appendix B: Computer Programs ......................................... 451
Appendix C: Abbreviations .................................................... 453
Index ........................................................................................ 459
=====PREFACE=====
T
his book is not a textbook on a subdiscipline of immunology. It is an
attempt to combine a wealth of information on the peptides associ
ated with MHC molecules, a wealth that has been accumulated since
1990 in an astonishing speed, much to the amazement of the authors
who witnessed the excitement around the discovery of the first few of
these peptides. This book has been written and put together for all those
somehow practically or theoretically involved with MH C-associated pep
tides-immunologists dealing with antigen-specific T-cell responses
involved in the defense against viruses, bacteria, parasites, and malig
nancies, or with T cell responses causing autoimmune disease and al
lergy, as well as in the development of T cells, that is, positive and nega
tive selection and T cell activation. Working with related problems our
selves, we felt the need for a handy source of information containing
not only MHC peptide motifs, MHC ligands and T cell epitopes, but
also the amino acid sequences of MHC molecules, in order to consider
the structural basis for MHC motifs, that is, the nature of the pockets.
Thus, this book is for our own use in the first place; since the number of
people dealing with MHC-associated peptides must be rather high (we
get quite a number of information requests) we thought that this book
should be useful and of interest to all those people.
The core of this book is the collection of motifs, ligands, and T cell
epitopes, and the relation of motifs to pocket composition. The mean
ing of this information in the context of the immune response is also
addressed, i.e., the events before ligand and MHC get together, and the
reaction of T cells against the final MHC/peptide complex. These parts,
unfortunately, had to be kept somewhat superficial in order to stay within
the size limit.
In collecting the data covered, we tried to be as accurate and as
comprehensive as possible. Given the vast amount of data to be screened,
however, we are afraid that some MHC ligands or even motifs have been
omitted inadvertently. We apologize in advance for this and also for any
errors that were overlooked in spite of very thorough cross-checking.
The T cell epitopes included should be looked at as a representative
selection rather than as a complete collection. Especially for class
II-restricted T cell epitopes, but also for HIV-epitopes, we found it dif
ficult to extract and judge for relevance all the peptide sequences re
ported to be recognized by T cells. The T cell epitopes that are covered,
as well as some additional aspects, are influenced by our personal bias,
e.g., MHC I -related items are usually given slightly more attention than
those connected with class II.
We gratefully acknowledge the impact and help of many individu
als who made this work possible: Jan Klein, to whom we owe our famil
iaritywith MHC; Kirsten Falk and Olaf Rotzschke, who started the work
on acid extraction of MHC-associated peptides in this laboratory and
the many other coworkers who have continued in this field; Gunther
Jung and his colleagues, who shared their expertise in peptide chemistry
with us; Niels Emmerich and Thomas Seitz, who extracted the new MHC
motifs, ligands and T cell epitopes from the literature, and organized the
new information; Thomas Friede, who checked part of the class II list
ings; Tilman Dumrese, who collected the minor H epitopes; Lynne Yakes,
who translated passages into English and carried out all the secretarial
work with the help of Petra Fellhauer; Patricia Hrstic for checking the
many tables; Hansjorg Schild, Tobias Dick, and Christian Munz for their
comments on Chapter 5 and for contributing illustrations; all the re
maining members of our group who contributed knowledge and ideas
in continuous discussion; Werner Mayer for critically reading chapter 2;
John Trowsdale and R. Duncan Campbell for contributing an excellent
figure on MHC gene organization; Steven Marsh for the preprint of the
'Nomenclature for factors of the HLA system, 1996'; all the editors and
authors who allowed the reproduction of materials and who shared un
published information, preprints, and reprints with us. In addition to
these individuals, we would like to thank the organizations supporting
our practical and theoretical work: Max Planck Institute for Biology,
Tubingen; German Cancer Research Center, Heidelberg; University of
Tubingen; Deutsche Forschungsgemeinschaft; Bundesministerium fur
Bildung, Wissenschaft, Forschung und Technologie; and Hoffman
La Roche.
Finally, we hope that our efforts in collecting, weighing, and orga
nizing data related to MHC function will be useful for the advance of
our understanding of the immune system, and for progress in preven
tion and treatment of infectious, autoimmune and malignant diseases.
Tubingen, March 1997
Hans-Georg Rammensee
Jutta Bachmann
Stefan Stevanovic
=====CHAPTER 1=======
History and Overview
HISTORY
T
he traits of MHC genes have been noticed as early as in the beginning of the 20th century:
a tumor grafted from a mouse to a genetically different mouse was rejected, whereas a
tumor transplanted to a mouse of the same strain was not rejected. Thus, the tumor was not
rejected on account of tumor-specific antigens but rather because of genetic differences be
tween the mouse strains involved.l It was not until 1936, however, that what is now known
as the MHC was discovered by Peter Gorer, then in London.2 He had produced a rabbit
anti-mouse serum for the sake of blood group studies. The reactivity of this serum, called
Nr. II, showed a striking correlation with tumor rejection: a tumor of the mouse strain A
was rejected by C57 mice and in a certain proportion of (A x C57)Fl x C57 backcross mice.
All mice not reactive with the serum rejected the tumor. On the other hand, those mice
rejecting the tumor developed antibodies with the same reactivity as rabbit serum Nr. II.
Thus, it appeared that what caused tumor rejection was a blood-group like antigen shared
by normal and tumor cells.2 Since this antigen was originally discovered because of its rec
ognition by rabbit anti-mouse serum Nr.II and because it resulted in tumor rejection, it was
called histocompatibility antigen 2 or H-2-not immediately, however, but about 10 years
later by George Snell and Gorer.l
George Snell then went on and started to isolate this and other histocompatibility genes
in the form of congenic strains. For this project, he replaced tumor transplantations by skin
grafting. This had two advantages: the rejection process was easier to follow and, more im
portantly, those mice not rejecting did survive and could be used for further breeding.
It turned out that the different mouse strains harbored a large number of such H genes;
the latter could be grouped, however, into those causing fast rejection of skin grafts (within
20 days) and those taking many weeks or months. Those H genes with the strong effect were
called major H genes, as opposed to the others, the minor H genes.3.4,5 When it was found
later that the major H genes of the mouse were all located within a cluster on chromosome
17, they were called the 'H-2 complex' and the corresponding gene groups in other species
(the next was the chicken) were called major histocompatibility complexes.
After Snell had received his Nobel Prize for his contribution to MHC genetics, he visited
Jan Klein in Tubingen and I, Hans-Georg Rammensee, was therefore fortunate enough to
meet him in person and to discuss my studies on minor H genes in wild mice with him.6
While the mouse MHC was discovered by a combination of transplantation studies
(histogenetics) and serological methods, the human MHC was discovered entirely by
MHC Ligands and Peptide Motifs, by Hans-Georg Rammensee, Jutta Bachmann, Stefan
Stevanovic. © 1997 Landes Bioscience.
2 MHC Ligands and Peptide Motifs
antibodies (reviewed in ref. I). In 1952, Jean called Immune response (Ir) genes.9 Using
Dausset in Paris found that some blood mice, H.O. McDevitt discovered that these
transfusion recipients produced antibodies genes correlated strongly with the H-2
able to agglutinate donor leukocytes.7 Rose haplotype. 10 Thus, MHC genes were likely
Payne at Stanford extended these studies and to have something to do with the regulation
in 1958 discovered that mothers produced of the immune response. The next major
antibodies against the paternal leukocyte achievement was the discoveryofMHC re
antigens expressed by their children. The striction by Zinkernagel and Doherty, then
same observation was made independently in Canberra, Australia. They studied the cel
by Jon van Rood in Leiden, who wrote a lular immune response of several mouse
most impressive PhD thesis about this dis strains against Lymphocytotropic
covery and the extensive serological studies choriomeningitis virus (LCMV). Target cells
it made possible. I am fortunate enough to infected with LCMV were only killed if they
be in possession of a signed copy of this, sharedMHC genes with the responder CTL.
"perhaps the most famous thesis ever writ Thus, the CTL had 'dual specificity'; they not
ten."l Like the other workers of that time, only recognized virus antigens on the in
van Rood had to struggle with extensive fected cells but also depended somehow on
checkerboard tables indicating which anti MHC molecules expressed on the infected
body lot had reacted with which leukocyte cell. I I A similar but less clear conclusion had
sample. It took a while and several Interna been drawn earlier upon the interaction
tional Histocompatibility Workshops until between T (helper) and B cells by Berenice
the conclusion was reached that all these leu Kindred (then at the University of Konstanz)
kocyte reactive antibodies that Dausset, and Donald Shreffler: "Therefore the H-2
Payne and van Rood worked on were the complex must play an active role in an en
counterparts of the mouse H-2 antigen, and during cooperation between bone marrow
thus, the human MHC molecules. Likewise, derived (B) cells and thymus-derived (T)
it took a number of years until the name of cells" (original citation see ref. 12). I was
the human MHC was fixed to be HLA-for fortunate to have known Berenice person
human leukocyte antigen. ally; she was at the Max-Planck-Institut fur
In the mid-sixties the word 'complex' in Biologie in Tubingen for the last 5 years of
the term MH C was seen to have been given her life (1980 to 1985), and lowe a good
righteously: no other genetic system in man deal of immunological knowledge to her, as
or mouse appeared to be more polymor well as fruitful advice as to which labora
phic. At the same time, nothing was known tory I should choose for a postdoctoral fel
about the physiological function of MHC lowship.
molecules; their involvement in allograft re Thus, in the mid-seventies it was known
jection could possibly not be their natural that both types of T cells-helpers and kill
function. Two major conceptual achieve ers-recognized their antigen somehow to
ments between 1965 and 1975 shed some gether with MHC molecules. To recognize
light on MHC function and indicated that this, new cell culture techniques, such as the
MHC molecules have something to do with mixed lymphocyte reaction and the 51Cr re
normal immune responses. When Hugh lease assay pioneered by Mishell and
McDevitt immunized mice with synthetic Dutton 13 and Brunner and Cerrottini,14 re
polypeptides produced by Michael Sela, spectively, were instrumental. Using both
some strains produced antibodies to certain techniques as in vitro correlates for allo
polypeptides but not others, and other rejection, the MHC products were classified
strains reacted with different patterns.8 into two categories, one more efficiently
Thus, the reactivity against a given (simple) stimulating CTL, the other more efficiently
antigen was genetically controlled-as also stimulating T cell proliferation in MLR. In
found by B. Benacerraf; genes involved were 1979, Jan Klein introduced the now famil-