Molecular Mechanisms of Lymphocyte 
Differentiation 
Stephen V. Desiderio, M.D., Ph.D. — Associate Investigator 
Dr. Desiderio is also Associate Professor of Molecular Biology and Genetics at the Johns Hopkins University 
School of Medicine. He received his undergraduate degree in Biology and in Russian from Haverford 
College and his M.D. and Ph.D. degrees from the Johns Hopkins University School of Medicine in 
biochemistry, and cellular and molecular biology. After a postdoctoral fellowship at the Massachusetts 
Institute of Technology with David Baltimore, he returned to Johns Hopkins. 
ONE remarkable feature of the immune sys- 
tem is its ability to recognize and respond to 
an extraordinary variety of foreign molecules, or 
antigens. This exquisite specificity is achieved 
through protein receptors, which bind tightly to 
specific antigens. Such receptors are found on 
the surfaces of two types of immune cells: B and T 
cells. 
One type of antigen receptor is the antibody 
molecule, or immunoglobulin. The site on the 
antibody molecule that binds to a specific anti- 
gen is genetically encoded by multiple short seg- 
ments of DNA. At the onset of development of the 
immune system, these DNA segments are located 
at separate places in the genome, but during the 
maturation of antibody-producing cells (B cells), 
segments are joined to form intact immunoglobu- 
lin genes. 
In addition to antibody, another class of anti- 
gen receptor is found on the surfaces of cells that 
mediate cellular immunity (T cells). The T cell 
receptor's antigen-binding site, like that of the 
antibody molecule, is encoded by multiple DNA 
segments that are brought together during T cell 
maturation. 
After their genes are assembled, the antigen re- 
ceptor molecules are expressed at the surfaces of 
B and T cells. Here, several interactions combine 
to trigger cell division and further maturation. 
These include the binding of antigens and special- 
ized hormones called lymphokines with their re- 
spective receptors. 
Lymphocyte Activation 
A major goal of our laboratory is to find out how 
specific antigens and growth factors trigger the 
activation of B and T cells. Biochemical evidence 
has long suggested that enzymes called tyrosine 
kinases might be intimately involved. These en- 
zymes regulate the activities of other proteins, 
and of each other, by adding regulatory chemical 
groups, phosphates, to specific sites. The kinases 
involved in B and T cell activation have, for the 
most part, proved elusive. We therefore set out to 
find new tyrosine kinase genes that are expressed 
in B or T cells, and we identified seven. Two are 
expressed only in immune cells, and we have 
concentrated on those. 
One of the genes resembles a growth- 
regulating gene called c-src. Unlike c-src, how- 
ever, which is turned on in many different kinds 
of cells, this new gene is only turned on in B cells 
and their developmental precursors. Accord- 
ingly, we call the gene blk, for B lymphoid ki- 
nase. The blk gene is activated early in B cell de- 
velopment and is expressed along with several 
proteins that are known to transmit signals across 
the B cell membrane, including the antibody 
heavy chain. 
When B cells develop into antibody-secreting 
or plasma cells, they no longer express these sig- 
nal transmission proteins or blk. This pattern sug- 
gests that the product of the blk gene interacts 
with a receptor that spans the B cell membrane 
and that senses the presence of antigen or a spe- 
cific growth signal. In the spleen, the protein en- 
coded by blk is found specifically in those loca- 
tions where resting B cells encounter antigen, 
reinforcing the idea that this kinase functions in 
the triggering of the B cell's immune response. 
How might extracellular signals activate the 
blk kinase? The kinase is inactivated by addition 
of a phosphate group to a specific site, and is 
activated when the phosphate is removed. If the 
target site on the blk kinase is mutated so that it 
cannot accept the inactivating chemical group, 
the enzyme is locked into the "on" state. Cells 
that contain this "on" version of the blk kinase 
grow in an unregulated way. Having an activated 
version of the blk kinase has made it easier to 
identify its targets. We have found one target to 
be an enzyme called phospholipase C-7 (PLC-7), 
a key component of the B cell activation pathway. 
Evidence from other systems suggests that PLC-7 
is activated by tyrosine kinases. We speculate that 
activation of the blk kinase in B cells activates 
PLC-7, initiating subsequent signaling events. 
The hormone interleukin-2 (IL-2) plays a cen- 
tral role in the immune response by inducing the 
multiplication of T cells. The binding of IL-2 to 
its receptor turns on a tyrosine kinase of unknown 
identity. We have recently identified six new tyro- 
sine kinase genes that are expressed in cells de- 
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