such as activated B cells and macrophages. CD28 
induces the activity of a nuclear complex, CD28RC, 
that binds to a site CD28 in the interIeukin-2 (IL-2) 
gene, CD28RE, and regulates promoter activity. 
During the past year the CD28-B7 interaction during 
physiologic stimulation of T cells by superantigen 
was shown to play a critical role in influencing IL-2 
promoter activity through interactions that depend 
on the CD28RE. (This work was supported by a 
grant from the National Institutes of Health.) Thus 
different signal transduction pathways regulated by 
distinct T cell surface molecules, the TCR and 
CD28, coordinately regulate the activation of the 
IL-2 gene. 
Dr. Weiss is also Ephraim P. Engleman Distin- 
guished Professor of Rheumatology and Professor 
of Medicine and of Microbiology and Immunol- 
ogy at the University of California, San Francisco. 
Articles 
Chan, A.C., Irving, B.A., Fraser, J.D., and Weiss, A. 
The f chain is associated with a tyrosine kinase 
and upon T-cell antigen receptor stimulation as- 
sociates with ZAP-70, a 70-kDa tyrosine phospho- 
protein. Proc Natl Acad Sci USA 88:9 1 66-9 1 70. 
Chan, A.C., Irving, B.A., and Weiss, A. 1992. New 
insights into T-cell antigen receptor structure and 
signal transduction. Curr Opin Immunol 4:24:6- 
251. 
Fraser, J.D., Newton, M.E., and Weiss, A. 1992. 
CD28 and T cell antigen receptor signal transduc- 
tion coordinately regulate interleukin 2 gene ex- 
pression in response to superantigen stimulation. 
f Exp Med 175:1131-1134. 
Margolis, B., Hu, P., Katzav, S., Li, W., Oliver, J.M., 
Ullrich, A., Weiss, A., and Schlessinger, J. 1992. 
Tyrosine phosphorylation of vav proto-oncogene 
product containing SH2 domain and transcription 
factor motifs. Nature 356:71-74. 
Weiss, A. 1991. Molecular and genetic insights into 
T cell antigen receptor structure and function. 
Annu Rev Genet 25:487-510. 
Weiss, A., Irving, B.A., Tan, L.K., and Koretzky, 
G.A. 1991 . Signal transduction by the T cell anti- 
gen receptor. Semin Immunol 3:313-324. 
LYMPHOCYTE-SPECIFIC GENES IN NORMAL AND NEOPLASTIC 
LYMPHOCYTE DIFFERENTIATION 
Irving L. Weissman, M.D., Investigator 
Lymphocyte Homing Receptors 
Lymphocytes are mobile cells that move from or- 
gan to organ via the blood and lymphatic vascular 
systems. Most mature blood lymphocytes are en 
route to lymphoid organs, which they enter within 
minutes after their appearance in the blood. 
Twenty-five years ago. Dr. Weissman and his col- 
leagues reported that new thymic emigrants enter 
lymphoid organs via organ-specific high-walled en- 
dothelial vessels (HEVs) ; and later, that both B and T 
lymphocytes enter lymphoid organs via common 
HEVs, but that lymphocytes use different homing 
receptors to bind to Peyer's patch versus lymph 
node HEVs. Using monoclonal antibodies, they 
identified and characterized the protein that makes 
up the major lymph node homing receptor (LNHR) 
molecule and the Peyer's patch homing receptor 
(PPHR) heterodimeric protein molecules. They 
then cloned the cDNA encoding mouse and human 
LNHRs and found that it was the first member of a 
new adhesion family called the selectins. 
During the past year. Dr. Weissman 's group 
cloned the genes encoding the two chains of the 
PPHR, a4 and ^7 . The a4 chain is found not only in 
the PPHR, but is part of the VLA4 molecule that the 
group showed to be involved in the binding of hema- 
topoietic precursors to thymic and bone marrow 
stromal cells and to inflamed endothelium. The 
cDNA encoding the a4 integrin contains sequences 
shared by other Ca^^-binding proteins that likely are 
involved in the noncovalent, Ca^^-dependent associ- 
ation of a4 with /37 or /3l chains. The cDNA encod- 
ing the |87 gene also has two putative Ca^^-binding 
domains, one an amino-terminal E-F hand sequence 
and the other a tetrad of EGF-similar sequences. 
Several regions of the murine and human aA 
cDNAs are conserved, most strikingly the transmem- 
brane and short cytoplasmic domains. (All three 
homing receptor genes [L-selectin, a4, ^1] contain 
transmembrane and cytoplasmic sequences con- 
served between mouse and human.) Transfection of 
the L-selectin leads to the homing of transfected 
lymphomas to lymph nodes but not Peyer's patches. 
Transfection of a4 or (il alone does not result in 
Peyer's patch homing, while transfection of both a4 
and |87 does. 
IMMUNOLOGY 367 
