Development of the Immune System 
Max D. Cooper, M.D. — Investigator 
Dr. Cooper is also Professor of Medicine, Pediatrics, and Microbiology at the University of Alabama at 
Birmingham. He received his M.D. degree and specialty training in pediatrics at Tulane Medical School 
and his postdoctoral training in immunology at the University of Minnesota. 
INFORMATION obtained from studies of im- 
mune system development in a variety of verte- 
brate species is used to explore diseases of the 
immune system in humans. We are particularly 
interested in the pathogenesis of immunodefi- 
ciency diseases and lymphoid malignancies. 
Comparative studies in birds and mammals ini- 
tially revealed the separate developmental path- 
ways of T and B lymphocytes, the rwo major types 
of immunocompetent cells. T cells provide help 
for antibody-producing B cells and are primarily 
responsible for immunity against viruses and 
fungi. 
The thymus is the source of T cells in all verte- 
brates, but the central tissue for B cell production 
may vary. In birds B cells are derived from the 
hindgut bursa of Fabricius, whereas in mammals 
they are generated in blood-forming organs, first 
the fetal liver and then the bone marrow. Multi- 
potent stem cells in these hematopoietic tissues 
serve as the precursors of T cells, B cells, and 
other types of blood cells. 
Inherited or acquired gene defects may specifi- 
cally alter growth or maturation of these cell 
lines to cause immune system dysfunction or 
malignancy. 
Genes encoding the T cell antigen receptors 
(TCR) and antibodies undergo controlled rear- 
rangement and expression in lymphoid cells 
beginning their development along T or B cell 
lineages. Other genes encode growth- and differ- 
entiation-promoting proteins and their receptors 
on T and B cells. An elaborate developmental pro- 
gram is thus responsible for the generation of 
millions of lymphocyte clones, each expressing a 
TCR or antibody molecule of different antigen 
specificity. These newly formed T and B cells are 
seeded via the bloodstream from the thymus or 
bone marrow to the spleen and other peripheral 
tissues, where they execute immune surveillance 
of foreign and self antigens. 
T Cell Development 
We have embarked on a comparative analysis of 
T cell development in representative avian, am- 
phibian, and mammalian species, prompted by 
an interest in the evolutionary strategy for gener- 
ating T cells that can discriminate between self 
and nonself and in seeking fresh clues to some of 
the unresolved mysteries of the human immune 
system. 
Our studies in birds reveal remarkable conser- 
vation of the pattern of T cell development found 
in mammals, including the sequential develop- 
ment of T cells bearing TCR of either 76 or a/3 
isotypes. While the functional role of those ex- 
pressing 76 TCR is still enigmatic, they are always 
generated first during ontogeny, may not undergo 
clonal selection during their intrathymic develop- 
ment, migrate preferentially to red pulp areas of 
the spleen and the epithelial lining of intestines, 
and constitute approximately one-third of the T 
cell pool in adult birds. 
The avian 76 T cells (also called TCRl cells) 
are capable of killing other cells, but unlike the 
a/3 T cells, are rarely triggered by recognition of 
conventional class II molecules of the major his- 
tocompatibility complex (MHC). Study of their 
physiological role is facilitated in birds by their 
relative abundance, and we hope to exploit the 
experimental ability to inhibit their development 
in a selective fashion. 
A fascinating aspect of the avian a/3 T cells is 
their development along two discrete sublin- 
eages identifiable by the TCR2 and TCR3 mono- 
clonal antibodies. In collaborative studies with 
Craig Thompson and his colleagues (HHMI, Uni- 
versity of Michigan), TCR2+ and TCR3' cells 
have been found to utilize different families of 
TCRjS variable-region genes (V/8): TCR2 cells use 
the V|8l genes, and the TCR3 cells use Vi82 genes. 
The avian \fi gene locus is thus simpler than the 
mammalian Vj8 locus, which contains many Vj8 
gene families. 
The avian V/31 and V/32 genes exhibit highly 
conserved sequences that characterize two major 
subgroups of the mammalian V|8 genes. Birds may 
thus provide a useful model system to study the 
functional significance of the generic V|S1 and 
V|82 gene families. Avian TCR(S diversity is cre- 
ated largely by nucleotide sequence variations in 
the joints berween the rearranged Vj8, D (diver- 
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