Activation ofCD4 T Cells 
bial infection or for immunity in its presence. We 
documented the importance of this by showing 
that tolerance to a self protein could be broken by 
inducing the expression of co-stimulator mole- 
cules on self antigen-reactive B cells. This last 
system may help to explain the role of specific 
pathogens in the initiation of autoimmunity. 
Parts of this work are also supported by grants 
from the National Institutes of Health. 
The T cell perceives the complex of foreign 
peptide and self MHC class II molecule with a 
receptor resembling the antigen-binding frag- 
ment of an immunoglobulin molecule. Although 
the most variable portion of this receptor lies in 
its central region, generated by the joining of sev- 
eral different gene segments, some variability 
is also expressed around the periphery of the 
ligand-binding site. This raises the question of 
what residues on the peptide-MHC complex are 
contacted by these peripheral antigen-binding 
loops on the T cell receptor. 
We recently showed that at least one of these 
loops makes contact with one side of the MHC 
molecule binding the foreign peptide. Detailed 
mutagenesis studies of both the T cell receptor 
and the MHC protein should soon reveal the de- 
finitive orientation of the T cell receptor to its 
ligand. 
The information derived from our studies on T 
cell activation is being applied to the analysis 
of a model autoimmune disease, the insulin- 
dependent diabetes mellitus that occurs sponta- 
neously in non-obese diabetic mice. We have iso- 
lated cloned T cells capable of invading the islets 
of irradiated mice and destroying (8-cells, produc- 
ing diabetes. In addition, we have identified 
other cells that appear to protect the islet. Analy- 
sis of the peptide-MHC ligands recognized by 
these various cell types, and of the events in- 
volved in their activation, should permit a better 
understanding of diabetes mellitus and lead to its 
specific immunomodulation. This work is also 
supported by a grant from the National Institutes 
of Health. Thus the basic science base of the labo- 
ratory is being applied to disease models in hopes 
of improving therapy in immunological diseases. 
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