Activation ofCD4 T Cells 
Charles A. Janeway, Jr., M.D. — Investigator 
Dr. Janeway is also Professor of Immunobiology at Yale University School of Medicine. He is a graduate of 
Harvard College (B.A., chemistry) and of Harvard Medical School. He had research training during 
medical school at the National Institute for Medical Research in London, England; postdoctoral training 
in internal medicine at the Peter Bent Brigham Hospital in Boston; and immunology research experience 
at NIH and the Biomedical Center in Uppsala, Sweden. Dr. Janeway was awarded the degree of Doctor 
Honoris Causa by the Copernicus Medical School of Jagellonian University in Cracow, Poland. 
THE critical event in most immune responses 
is the activation of specific CD4 T lympho- 
cytes. When these cells are lost, as happens in 
AIDS, the immune system can no longer defend 
the host against infection. Our laboratory is study- 
ing the mechanism by which these cells become 
active. This is a complex process involving 
changes in both the cell that presents the activat- 
ing antigen and the T cell itself. 
The process requires two events. First, the 
antigen-specific receptor on the T cell must en- 
counter its appropriate ligand on the surface of 
an antigen-presenting cell. This results in spe- 
cific signaling of the T cell that will cause it to 
become immunologically inert, or anergic. Aner- 
gic T cells cannot mount responses. In order for 
antigen recognition to lead to an eff'ective re- 
sponse, the CD4 T cell must receive a second sig- 
nal or co-stimulator. Studies in our laboratory 
have characterized the chemical structure of sev- 
eral peptides that are bound by class II molecules 
of the major histocompatibility complex (MHC) 
and thus recognized by CD4 T cells. Second, we 
have identified two molecules expressed on anti- 
gen-presenting cells that are capable of co-stimu- 
lating the activation of resting, naive CD4 T cells. 
Finally, we have shown that a single cell must 
present both the peptide-MHC complex and the 
co-stimulator in order for normal CD4 T cells to 
be activated eff'ectively. 
The ligand recognized by the receptor on CD4 
T cells consists of a peptide fragment of a foreign 
protein antigen bound to a class II MHC-encoded 
molecule. Our laboratory has isolated peptides 
from such molecules and characterized their 
structure. These molecules are approximately 15 
amino acids in length and have specific residues 
at certain positions for each different MHC class 
II molecule. Although the cleavage of these frag- 
ments from the native proteins has not been char- 
acterized, the results of our analysis suggest that 
the MHC molecule protects the peptide fragment 
from further proteolytic degradation. 
A striking result in these studies was the finding 
that 1 2 percent of normal MHC class II molecules 
on antigen-presenting cells were in complex 
with a particular self peptide. As a number of sim- 
ilarly dominant peptides were observed, it seems 
possible that the total complexity of self peptides 
to which the immune system must be tolerant 
may be quite limited. This is important, as it al- 
lows the maximum complexity of foreign pep- 
tides to be recognized. 
Of even greater interest is the finding that this 
specific complex is found richly represented on 
cells in the thymic medulla, including bone 
marrow-derived cells, but is present only at very 
low levels on thymic cortical epithelium. These 
two tissues are known to carry out distinctive 
events involving self MHC-peptide complexes in 
the maturation of T cells within the thymus. The 
finding that a self peptide is unevenly distributed 
between these cell types suggests that T cell de- 
velopment occurs under different selecting envi- 
ronments for different processes. The antibody 
recognizing this processed self peptide bound to 
self MHC class II will allow our laboratory to 
probe this process in living animals. The same 
technology is now being applied to the analysis of 
autoantigens and peptides generated by intracel- 
lular infectious agents such as Salmonella 
typhimurium. 
In addition to ligation of the receptor, the same 
antigen-presenting cell must also express co- 
stimulatory molecules on its surface in order to 
activate CD4 T cells optimally. We have con- 
firmed the importance of the B7 molecule, a 
known co-stimulator of human T cells, in the ac- 
tivation of murine CD4 T cells and have discov- 
ered that the heat-stable antigen can also serve as 
a co-stimulator for murine T cells. Either of these 
proteins, transfected into fibroblasts, can confer 
their CD4 T cell-activating properties. More- 
over, the two proteins act in a strongly synergistic 
manner on normal antigen-presenting cells to 
promote the proliferation of CD4 T cells. 
Finally, we have shown that B7 expression is 
regulated in parallel with co-stimulatory activity 
when B lymphocytes respond to a variety of mi- 
crobial products. This regulated behavior of co- 
stimulators allows B cells to present antigen to 
CD4 T cells for tolerance in the absence of micro- 
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