ACTIVATION OF THE CD4 T CELL 
Charles A. Janeway, Jr., M.D., Investigator 
Studies in Dr. Janeway's laboratory focus on the 
activation of CD4 T cells in normal adaptive im- 
mune responses as well as in selected animal models 
of autoimmune disease. Studies cover several 
aspects of the basic process of CD4 T cell activation 
that have application to the disease models. 
The Ligand for the CD4 T Cell Receptor 
CD4 T cells recognize a molecular complex con- 
sisting of a peptide fragment of antigen bound in the 
groove of a class II molecule of the major histocom- 
patibility complex (MHC). This complex ligand has 
been inferred from many studies, but only recently 
has it been characterized directly. Dr. Janeway's 
group has isolated and sequenced several naturally 
processed peptide fragments bound to the groove of 
several different MHC class II molecules. These 
dominant peptides are distinct in structure from 
those isolated from MHC class I molecules by other 
laboratories, being longer by several amino acids 
and differing in length at both ends. These length 
differences, however, do not markedly affect the 
specificity of T cell recognition, which is focused 
on the central region of the peptide. 
The peptides show specific residues at two or 
more positions within the sequence, and these are 
likely involved in binding to MHC molecules. The 
data are compatible with the groove on the MHC 
class II molecule being similar to that of MHC class 
I, but differing at the ends, where MHC class II mole- 
cules are likely to be open, allowing the bound pep- 
tide to extend out at one or both ends. The T cell 
receptor (TCR) seems likely to focus only on the 
central region of 8-10 amino acids that includes 
MHC-binding residues and those that interact with 
the TCR central region. The technique used by Dr. 
Janeway's group should provide a novel means of 
identifying major peptide epitopes in infectious dis- 
eases and autoimmunity, and this is being tested 
in Salmonella typhimurium infection and in 
diabetes-prone mice. Moreover, the definition of 
peptide motifs by direct sequencing of MHC class 
Il-associated peptides provides an alternative ap- 
proach to searching for peptide epitopes within 
proteins. (A grant from the National Institute of Al- 
lergy and Infectious Diseases, National Institutes of 
Health, provided partial support for this project.) 
Rules for Antigen Presentation by MHC 
Class II Molecules 
Based on the isolation of peptides from MHC mol- 
ecules and other studies, several rules that govern 
presentation of peptides by MHC class II molecules 
have been derived. These are as follows. First, the 
peptide donor must be abundant in the processing 
compartment; membrane-associated proteins that 
are internalized appear to be particularly attractive 
peptide donors. Second, the peptides have a vari- 
able length, with a mean of 16 amino acid residues 
and a range of 1 3 to 22 residues in the hands of the 
Janeway laboratory. Third, the peptide must have 
certain amino acids at particular positions to allow 
it to bind stably to the MHC class II molecule that 
will transport it to the cell surface. Finally, the pep- 
tide must be producible from the protein in the pro- 
cessing compartment. 
Dr. Janeway and his colleagues have discovered a 
self protein whose carboxyl-terminal peptide is po- 
tently immunogenic in mice; that is, the mice are 
not tolerant to the self peptide. T cells specific for 
the peptide do not recognize the parent protein, ap- 
parently because of a failure to generate the pep- 
tide. The same peptide from the foreign homologue, 
differing by two amino acids from self, is readily 
processed from the native protein. Thus a pro- 
tein must be able to yield the peptide in order 
for that peptide to be recognized. Working out the 
rules for processing using this system will be very 
interesting. 
Distribution of Dominant Peptide Epitopes 
and Its Implications for T Cell Development 
One of the central mysteries of immunology is the 
selection of the repertoire of TCRs. From a random, 
clonally distributed repertoire expressed by early 
developing T cells in the thymus, only those that can 
recognize peptides presented by self MHC mole- 
cules mature. Moreover, potentially harmful T cells 
recognizing self peptides bound by self MHC mole- 
cules are deleted from this surviving pool. Thus ma- 
ture T cells are self MHC restricted and self tolerant. 
The puzzle is how a receptor interacting with self 
MHC molecules binding self peptides can signal for 
positive selection at one stage of development and 
then for negative selection at a later phase. Such a 
system would seem to leave no cells available for 
export. Thus there must be some difference in the 
response of the cell to the same signal, or in the 
ligand itself. 
Having identified self peptides bound to self MHC 
molecules. Dr. Janeway's laboratory has used a 
unique monoclonal antibody that recognized one 
such complex to examine its abundance and distri- 
IMMUNOLOGY 337 
