elimination of the pathogen. If antigen is not pres- 
ent, then the effector cells either enter afferent lym- 
phatics and thus return to the blood, or they die in 
the tissues. As Dr. Janeway's studies actually used 
cells reactive to a self antigen, similar consider- 
ations also apply to the homing of autoreactive T 
cells to tissues and v^^ould presumably apply to graft 
rejection as well. 
Insulin-Dependent Diabetes Mellitus, 
a Model Autoimmune Disease 
CD4 T cells play a crucial role in autoimmune 
diabetes, which Dr. Janeway's laboratory is studying 
through use of the spontaneous diabetes seen in the 
nonobese diabetic (NOD) mouse. Cloned islet- 
specific CD4 T cells are required to transfer disease, 
but only if cloned islet-specific CDS T cells are also 
transferred. More recently Dr. Janeway's laboratory 
has shown that islets of diabetic mice contain not 
only T cells that can destroy pancreatic (3 cells, caus- 
ing diabetes, but also CD4 T cells that can transfer 
protection against diabetes. These protective T cells 
are of great interest, as their specific activation 
might be a means of disease prevention. Thus such 
cells are currently under intensive study. 
A second area of study is the protection afforded 
NOD mice by the MHC class II I-E transgene. Dr. 
Janeway, in collaboration with the laboratory of Dr. 
Richard Flavell (HHMI, Yale University), has shown 
that this protection requires I-E expression on pe- 
ripheral antigen-presenting cells. These cells play a 
role in inducing self tolerance, and it is interesting 
in this regard that the cloned T cell lines that 
transfer diabetes express TCRs encoded in V/31 gene 
segments. T cells bearing such receptors are promi- 
nent in prediabetic islets and have a restricted set of 
sequences, suggesting a role for specific receptors 
in this disease. Whether T cells of this type are de- 
leted by I-E expressed on peripheral antigen- 
presenting cells is now being tested, as this could 
provide a simple explanation of I-E's protective ef- 
fect. Finally, the superantigen SEA (staphylococcal 
enterotoxin A) accelerates diabetes in NOD mice 
and also stimulates T cells expressing VjSl -encoded 
receptors. Thus a careful analysis of V/31 expression 
is another focus of this program. (This work is sup- 
ported in part by a grant from the National Institute 
of Diabetes and Digestive and Kidney Diseases, Na- 
tional Institutes of Health.) 
The NOD mouse shares a unique feature of its 
MHC class II molecules with most human diabetics: 
the absence of an aspartic acid residue at position 57 
on the |8 chain. To examine the nature of peptides 
bound to NOD MHC class II molecules. Dr. Janeway 
and his colleagues have purified this complex, 
eluted peptides, and sequenced them. These pep- 
tides show a distinctive peptide motif, one feature 
of which is an acidic residue near the carboxyl ter- 
minus. Peptides eluted from three other MHC class 
II molecules that have aspartic acid at position 57 of 
the |8 chain do not have an acidic residue at this site. 
Thus a unique islet autoantigen may bind much bet- 
ter to non-aspartic 57 MHC class II molecules be- 
cause the peptide has an acidic residue that is pre- 
vented from binding by the aspartic acid at residue 
57. This hypothesis is being tested by site-directed 
mutagenesis, synthetic peptide binding, and further 
peptide-sequencing studies. 
In summary, studies in Dr. Janeway's laboratory 
focus on the activation of CD4 T cells, from the gen- 
eration of ligands and co-stimulatory molecules on 
antigen-presenting cells through the precise nature 
of TCR binding to these complexes, to more diffi- 
cult questions of autoimmune disease and lympho- 
cyte homing. They seek to explain the phenomena 
of adaptive immunity in T cells and its failure in 
autoimmune disease. 
Dr. Janeway is also Professor of Immunobiol- 
ogy at the Yale University School of Medicine and 
of Biology at Yale University. 
Articles 
Dianzani, U., Redoglia, V., Malavasi, F., Bragardo, 
M., Pileri, A., Janeway, C.A., Jr., and Bottomly, 
K. 1992. Isoform-specific associations of CD45 
with accessory molecules in human T lympho- 
cytes. Eur J Immunol 22:365-371. 
Dianzani, U., Shaw, A., Al-Ramadi, B.K., Kubo, R.T., 
and Janeway, C.A., Jr. 1992. Physical associa- 
tion of CD4 with the T cell receptor. J Immunol 
148:678-688. 
Hong, S.-C, Chelouche, A., Lin, R., Shaywitz, D., 
Braunstein, N.S., Glimcher, L., and Janeway, 
C.A., Jr. 1992. An MHC interaction site maps to 
the amino-terminal half of the T cell receptor a 
chain variable domain. Cell 69:999-1009. 
Janeway, C.A., Jr. 1991- The co-receptor function 
of CD4. Semin Immunol 3: 1 53-160. 
Janeway, C.A., Jr. 1991. Selective elements for the 
V/3 region of the T cell receptor: Mis and the bacte- 
rial toxic mitogens. Adv Immunol 50:1-53. 
Janeway, C.A., Jr. 1991 . To thine own self be true. 
Curr Biol 1:239-241. 
Janeway, C.A., Jr. 1992. The case of the missing 
CD4s. Curr Biol 7 -.559-561. 
Janeway, C.A., Jr. 1992. The immune system 
evolved to discriminate infectious nonself from 
noninfectious self. Immunol Today 13:1 1-16. 
Janeway, C.A., Jr. 1992. The T cell receptor as a 
multicomponent signalling machine: CD4/CD8 
IMMUNOLOGY 339 
