SELECTIVE INFLUENCES ON T CELL DEVELOPMENT 
Charles A. Janeway, Jr., M.D., Investigator 
Studies in Dr. Janeway's laboratory are focused 
on environmental influences on the development 
of specificity in T lymphocytes. During the past 
year, progress in several areas has led to the formu- 
lation of new hypotheses about several of these en- 
vironmental influences and the development of a 
new model of T cell development. This model seeks 
to account for the central mystery in this process, 
the generation of a repertoire of receptors that is 
selected for the recognition of foreign antigens pre- 
sented by self major histocompatibility complex 
(MHC) molecules, u^hile at the same time being un- 
responsive to these same MHC molecules or self 
peptide fragments bound to these MHC molecules. 
This model is based on several new findings. 
I. CD4: A Physical Component of the T Cell 
Receptor. 
The cell surface molecule CD4 is expressed on T 
cells that recognize self class II MHC molecules. 
Studies in Dr. Janeway's laboratory have shown 
that CD4 physically associates with the T cell re- 
ceptor during recognition of antigen: class II MHC 
complexes and that this association potentiates sig- 
naling through the receptor by ~100-fold. Cross- 
linking CD4 in the context of the T cell receptor ac- 
tivates tyrosine kinases that phosphorylate novel 
cytoplasmic substrates that are now being charac- 
terized. Because CD4 interacts in a defined orienta- 
tion with both class II MHC molecules and the T 
cell receptor, the orientation of the T cell receptor 
and class II MHC molecules must also be fixed. Dr. 
Janeway has proposed the term co-receptor to de- 
scribe the function of CD4 and of the class I MHC- 
binding molecule CDS. 
II. Orientation of T Cell Receptor:MHC Interaction. 
Antigen-presenting cells express a class of mole- 
cules Dr. Janeway terms co-ligands. Dr. Janeway's 
laboratory has studied the Mis co-ligands and intro- 
duced the staphylococcal enterotoxins as models 
for the analysis of Mis co-ligands. Staphylococcal 
enterotoxins were shown to bind to class II MHC 
molecules and the vp segment of the T cell recep- 
tor and to stimulate T cell activation directly. Staph- 
ylococcal enterotoxins also induce clonal deletion 
of T cells bearing certain Vp-encoded receptors. 
This assay was used to show that tolerance medi- 
ated by such substances is more sensitive than is ac- 
tivation, allowing a margin for safety in the clonal 
deletion process in the thymus. Co-ligands also can 
potentiate antigen presentation. Because co-ligands 
also bind specifically to the T cell receptor and the 
class II MHC molecule, they further orient the T 
cell receptor: ligand interaction. 
III. Co-ligand-Driven Clonal Deletion and Preven- 
tion of Murine Diabetes. 
Dr. Janeway's laboratory has isolated cloned T 
cell lines that will transfer autoimmune diabetes to 
syngeneic, irradiated mice. Both a CD4 and a CDS T 
cell are required to transfer diabetes. Both cloned 
lines express T cell receptors encoded by V(35 
genes. T cells whose receptors are encoded by VP5 
genes are deleted in mice expressing I-E class II 
MHC molecules and a suitable co-ligand, and diabe- 
tes-prone mice expressing I-E do not develop dis- 
ease. Moreover, these cloned lines can cause dis- 
ease in I-E mice, demonstrating no protective effect 
of I-E on host tissues. Thus the protective effect of 
I-E is almost surely due to its ability to present a co- 
ligand for deletion of diabetes-inducing, Vp5-bear- 
ing T cells. Finally, depletion of vp5-bearing T cells 
from T cell populations obtained from diabetic 
mice eliminates their ability to transfer disease to 
normal recipients. 
IV Aberrant Expression of Self Peptides in Thymic 
Cortical Epithelium. 
Positive selection of the T cell repertoire occurs 
on thymic cortical epithelium. Dr. Janeway's labora- 
tory has prepared a monoclonal antibody to a self 
peptide bound to a self class II MHC molecule. This 
complex is expressed by all class II MHC-express- 
ing cells except thymic cortical epithelium. This 
suggests that the ligands involved in positive selec- 
tion are molecularly distinct from those involved in 
negative selection or peripheral T cell activation. 
This may explain how T cells can be positively se- 
lected by self MHC and yet have specificities not 
found on peripheral cells that would cause clonal 
deletion. 
V Involvement of Crosslinking and Conformational 
Change of the T Cell Receptor in T Cell Activation. 
Dr. Janeway's laboratory has extensively analyzed 
T cell activation by monoclonal anti-T cell receptor 
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