Antigen-Specific T Cell Receptors 
Dennis Y.-D. Lob, M.D. — Associate Investigator 
Dr. Lob is also Professor of Medicine, Genetics, and Microbiology at Wasbington University Scbool of 
Medicine and Associate Pbysician at Barnes Hospital, St. Louis. He received his undergraduate degree in 
biology and cbemical engineering from the California Institute of Technology and his medical degree from 
Harvard Medical Scbool. He took a clinical residency in internal medicine at the Peter Bent Brigbam Hos- 
pital, Boston, and then studied as a postdoctoral fellow with David Baltimore at the Massachusetts Insti- 
tute 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. Its 
critical role in maintaining health is well typified 
in the acquired immune deficiency syndrome 
(AIDS) , in which destruction of a specific portion 
of the immune system results in a 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 in- 
vading organisms or tissue destruction, as seen 
in transplantation rejection and autoimmune 
phenomena. 
During the past few years, my laboratory has 
concentrated on identifying the genetic elements 
that encode the TCR genes. Recently we have 
shifted our efforts to study the function of T cells 
in the intact animal. Two important questions 
were addressed. 1) Why are we tolerant of our 
own tissues and organs? 2) Why are transplanted 
organs rejected readily (unless they are carefully 
cross-matched)? We have used both recombinant 
DNA technology and our ability to create trans- 
genic mice (mice with cloned genes incorpo- 
rated in their own chromosomes) to study these 
questions. Two kinds of transgenic mice have 
been created. One kind bears transgenic TCR 
genes; the other has transgenic major histocom- 
patibility complex (MHC) genes (a marker that 
distinguishes us individually during transplanta- 
tion). By introducing these genes back into the 
mouse itself and into the mouse germline, we can 
determine how normal T cells develop by study- 
ing 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 
were not physically eliminated but are function- 
ally paralyzed. These studies allow us to lay the 
foundation to study how T cells acquire 
self-tolerance. 
Most recently, we have developed a new gener- 
ation of TCR transgenic mice in which we can 
induce massive cell death when the appropriate 
antigen is administered in vivo. These studies 
prove that clonal elimination of self-reactive 
cells is indeed mediated by programmed cell 
death. These new approaches should shed insight 
into the development of self-tolerance and the 
mechanism of programmed cell death during de- 
velopment. Since distinguishing what is self and 
nonself is a central problem in immunology, we 
hope these studies will increase understanding 
of transplantation rejection and autoimmune 
phenomena. 
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