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. After doing an internship and residency at 
the Peter Bent Brtgham Hospital, Boston, he spent eight years as a research medical officer in the United 
States Navy. During this time, he held laboratory positions 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 types of cells: 1) the B cell, which se- 
cretes antibodies that bind to and target foreign 
substances for elimination by the immune sys- 
tem, and 2) the T cell, which is capable of pro- 
ducing a variety of molecules, known as lympho- 
kines, that regulate the functions of other cells 
involved in immune responses. T cells are also 
capable of identifying cells expressing foreign 
proteins and destroying them by cell-mediated cy- 
totoxicity. 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. 
The central role of the lymphoid immune sys- 
tem in the natural resistance to infectious dis- 
eases has been demonstrated by the infectious 
problems encountered by patients with both con- 
genital and acquired immunodeficiency syn- 
dromes. Many of the serious infectious and neo- 
plastic complications associated with the 
acquired immune deficiency syndrome (AIDS) 
are the result of depletion of the helper cells, a 
subset of T cells. A better understanding of the 
molecular mechanisms associated with genera- 
tion of both B and T cells during development 
would aid in our ability to understand and treat 
various immunodeficiencies. 
B cells derive their name from the bursa of Fab- 
ricius, a developmental organ in birds that is re- 
quired for the generation of mature B cells. Mam- 
mals lack a bursa of Fabricius but still appear to 
be able to generate a B cell immune system. Over 
the past several years, our laboratory has investi- 
gated the role of this organ in B cell development 
in the chicken. We are attempting to characterize 
differences in the generation of B cells in mam- 
mals and avian species to account for this lack in 
mammals. The major role of the B cell immune 
system is to generate the approximately 10 mil- 
lion different antibody molecules needed to pro- 
tect the body from foreign substances. 
Our studies have helped demonstrate that the 
primary molecular mechanism by which chick- 
ens generate this large number of different anti- 
body molecules is different from that used by 
mammals. Antibody diversity in the chicken is 
achieved by gene conversion, a molecular mecha- 
nism that occurs during B cell development in 
the bursa of Fabricius and that requires the induc- 
tion of cell proliferation within the bursa of Fab- 
ricius. We have begun to characterize the require- 
ments for this proliferation. These studies have 
led to insights into how genes encoding immuno- 
globulin molecules are initially assembled and 
modified during development. 
It has recently been shown that immunoglobu- 
lin gene conversion also occurs in mammals. The 
molecular events that are used to generate gene 
conversions in chickens may also be used to 
create the somatic mutations that arise in mam- 
malian immunoglobulin genes during B cell de- 
velopment. Somatic mutations have been impli- 
cated in enhancing the ability of a cell to respond 
to foreign substances but also in the development 
of leukemia and lymphomas. Our studies in the 
chicken should teach us more about this impor- 
tant but potentially dangerous process. 
T cells have been divided in the past into two 
major subsets — helper T cells, which produce 
the lymphokines that regulate immune re- 
sponses, and cytotoxic T cells, which can kill 
cells expressing foreign proteins. A number of 
years ago the molecular requirements for the 
grovvT:h and expansion of cytotoxic T cells were 
defined. Those studies led to the discovery of the 
lymphokine interleukin-2 (IL-2) and, subse- 
quently, to a variety of therapeutic trials using 
IL-2 to increase cell-mediated immunity in pa- 
tients with cancer. Unfortunately, conditions for 
the growth of helper T cells have yet to be de- 
fined. An understanding of the molecular mecha- 
nisms that regulate the function and proliferation 
of helper T cells is now of particular interest, 
since it is helper T cells that are deficient in pa- 
tients with AIDS. 
Over the past several years, we have been in- 
vestigating molecular mechanisms that regulate 
helper T cells. We have defined a helper T cell 
activation pathway that appears to regulate the 
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