Molecular Regulation of Lymphoid Cell Growth 
and Development 
Craig B. Thompson, M.D. — Associate Investigator 
Dr. Thompson is also Associate Professor of Internal Medicine and of Microbiology and Immunology at the 
University of Michigan Medical School. He received his undergraduate degree from Dartmouth College 
and his medical degree from the University of Pennsylvania. Following an internship and residency at the 
Peter Bent Brigham Hospital, Boston, he spent eight years as a research medical officer in the United States 
Navy. During this time, he conducted his research at Boston University, the Uniformed Services University 
of the Health Sciences, the Fred Hutchinson Cancer Research Center, and the Naval Medical Research 
Institute. 
THE lymphoid immune system comprises two 
major cell types: the T cell, which identifies 
and destroys cells expressing foreign proteins; 
and the B cell, which secretes antibodies that 
bind to foreign substances, targeting them for 
elimination. The central role of the system in the 
natural resistance to infectious diseases is demon- 
strated by the infections encountered by patients 
with immunologic deficiencies. Many of the seri- 
ous infectious and neoplastic complications asso- 
ciated with the acquired immune deficiency syn- 
drome (AIDS) are the result of depletion of the 
helper T cells. 
A better understanding of the molecular 
mechanisms associated with generation of both B 
and T cells during development would aid in our 
ability to understand and treat various immunode- 
ficiencies. The goals of our laboratory are to un- 
derstand the molecular events associated with 
the development of the lymphoid immune sys- 
tem and to define the mechanisms by which the 
functions of these cells are controlled. 
T cells are divided into two major subsets: 
helper T cells, which produce the lymphokines 
that regulate immune responses, and cytotoxic T 
cells, which can kill cells expressing foreign pro- 
teins. The cooperation of these two cell types is 
needed for the immune system to reject a foreign 
cell or a cell bearing foreign proteins. Initiation 
of a helper T cell response requires activation of 
the T cell receptor by foreign histocompatibility 
genes. Recent evidence suggests, however, that T 
cell receptor activation alone does not lead the 
helper cell to produce sufficient amounts of lym- 
phokines to initiate an immune response. Addi- 
tional co-stimulatory signals are required. 
Previously we showed that the CD 2 8 receptor 
expressed on helper T cells serves as a surface 
component of a signal transduction pathway that 
can enhance T cell lymphokine production. In 
vitro, interaction of CD28 with its natural ligand 
B7, expressed on activated B cells or macro- 
phages, can act as a co-stimulus to such enhance- 
ment. Now we have evidence that CD28 activa- 
tion of primary T cells is also a required 
co-stimulatory event in the initiation of a cell- 
mediated immune response. 
We have investigated the role of the CD 2 8 
pathway in allogenic responses by using a soluble 
CD28 receptor homologue termed CTLA-4-Ig, 
produced by our collaborator Peter Linsley. This 
protein is a recombinant that displays an affinity 
for the CD28 ligand, B7, approximately 20-fold 
higher than does cell-bound CD28. Therefore it 
acts as a competitive inhibitor of CD28 engage- 
ment. In vitro, CTLA-4-Ig was found to be able to 
inhibit completely the ability of cells from one 
rat strain to respond against cells from another. 
Based on these data, the ability of CTLA-4-Ig to 
prevent the induction of organ graft rejection was 
tested in a cardiac transplant model. Trans- 
planted hearts in control animals receiving no im- 
munotherapy are rejected within one week of 
transplantation. In contrast, when activation of 
the CD28 pathway is blocked by daily administra- 
tion of CTLA-4-Ig, rejection of the cardiac trans- 
plant is prevented. 
These data support the hypothesis that helper T 
cell co-stimulation by the CD28-ligand, B7, is a 
required event in the initiation of a T cell- 
mediated immune response. Furthermore, the 
work suggests that preventing B7 activation of a T 
cell may not only help to prevent transplant re- 
jection but may also help to decrease the severity 
of autoimmune diseases such as rheumatoid ar- 
thritis. Work to address this issue is being 
planned. 
The major role of the B cell immune system is 
to generate the approximately 10 million diff'er- 
ent antibody molecules needed to protect the 
body from foreign substances. B cells derive their 
name from the bursa of Fabricius, a developmen- 
tal organ in birds that is required for B cell matura- 
tion. Mammals lack this organ but are still able to 
generate a B cell immune system. Over the past 
several years, our laboratory has investigated the 
role of the bursa in B cell development in the 
chicken. We are attempting to characterize dif- 
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