The Biology of T Lymphocyte Development 
Dennis Y.-D. Loh, M.D. — Associate Investigator 
Dr. Loh is also Professor of Medicine, Genetics, and Molecular Microbiology at Washington University 
School of Medicine and Chief of the Division of Allergy and Immunology and Associate Physician at 
Barnes Hospital, St. Louis. He received his undergraduate degree in biology and chemical engineering from 
the California Institute of Technology and his medical degree from Harvard Medical School. After finishing 
his clinical residency in internal medicine at the Peter Bent Brigham Hospital, Boston, he studied as a 
postdoctoral fellow with David Baltimore at the Massachusetts Institute of Technology. 
THE immune system is involved intimately in 
our body's defense against invading microor- 
ganisms and tumors. In addition, it plays a central 
role in organ graft rejection and autoimmune dis- 
eases such as systemic lupus erythematosus, 
rheumatoid arthritis, and diabetes. Its critical 
role in maintaining health is best manifested in 
the acquired immune deficiency syndrome 
(AIDS) , in which destruction of a specific portion 
of the immune system results in a potentially fatal 
disease. 
Our investigation is focused on the molecular 
mechanisms that allow normal and abnormal de- 
velopment of the antigen-specific T cells. T cells 
are those lymphocytes (a type of white cell) that 
depend on the presence of the thymus gland for 
maturation. An antigen may be viewed as any 
marker that these cells recognize. T cells are 
thought to play a central role in the regulation of 
the immune response. T cells recognize antigens 
by means of a cell surface structure called the T 
cell receptor (TCR) . The genes that are responsi- 
ble for the expression of the TCR undergo DNA 
gene rearrangement and gene activation specifi- 
cally in the thymus during the individual's early 
development. Once the TCR is expressed as pro- 
tein, it is the interaction of the TCR with its anti- 
gen that triggers the activation of T cells, result- 
ing in an immune response. The ultimate result of 
such a response may be either defense against 
invading organisms or tissue destruction, as 
seen in transplantation rejection and autoim- 
mune phenomena. 
My laboratory initially concentrated on identi- 
fying the genetic elements that encode the TCR 
genes. We then shifted our efforts to study the 
function of T cells in the intact animal, especially 
during its development. Two important ques- 
tions were addressed. 1) Why are we tolerant of 
our own tissues and organs? 2) Why are trans- 
planted organs rejected readily (unless they are 
carefully cross-matched)? We have used both re- 
combinant DNA technology and our ability to 
create transgenic mice (mice with cloned genes 
incorporated in their own chromosomes) to 
study these questions. Two kinds of transgenic 
mice have been created. One kind bears trans- 
genic TCR genes; the other has transgenic major 
histocompatibility complex (MHC) genes (a 
marker that distinguishes us individually during 
transplantation) . By introducing these genes back 
into the mouse itself and into the mouse germ- 
line, we can determine how normal T cells de- 
velop by studying how the TCR and MHC interact 
during development. 
This strategy has been very successful. By creat- 
ing mice of appropriate genetic background, we 
discovered that T cells that are self-recognizing 
and hence self-reactive are deleted in the thymus 
during development. This implies that part of 
self-tolerance is accomplished by physical elimi- 
nation of self-reactive T cells. Using mice con- 
taining transgenic MHC, we showed a second 
mechanism of self-tolerance that does not involve 
physical deletion. In this case, self-reactive cells 
are not physically eliminated but are functionally 
paralyzed. These studies allow us to lay the 
foundation to study how T cells acquire self- 
tolerance. Since distinguishing what is self and 
nonself is a central problem in immunology, we 
hope that these studies will lead to a better un- 
derstanding of transplantation rejection and au- 
toimmune phenomena. 
The detailed study of T cell development also 
allows us to investigate the cellular and molecu- 
lar requirements of normal cellular developmen- 
tal processes. For example, we still do not under- 
stand how certain T cells are eliminated while 
others are selected to survive. To elucidate the 
exact molecular mechanisms that underlie this 
highly regulated process, we have most recently 
focused on the structural and signaling basis that 
controls differential cell fate of the developing 
thymocytes. To do this we have combined the 
two powerful technologies of transgenic mice 
and gene knock-out mice. In the latter mice, se- 
lected genes can be targeted to be destroyed in 
the germline so that mice bearing selected muta- 
tions can be created. Once these mice have been 
prepared, mutant molecules can be introduced to 
replace the "knocked-out" genes. Current efforts 
are concentrated on signaling molecules such as 
CD4 and CDS that are important in T cell devel- 
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