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 investigate 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 two major types 
of immunocompetent cells. T cells provide help 
for antibody-producing B cells and are primarily 
responsible for immunity against viruses and 
fungi. We wish to know whether the thymus is 
the only source of T cells in vertebrates or 
whether they may also arise in other tissues. 
The central tissues may vary for production of B 
cells, the source of antibodies. In birds, immuno- 
globulin (Ig) -bearing B cells are derived from the 
hindgut bursa of Fabricius, whereas in mammals 
such cells are generated in blood-forming organs, 
mainly the fetal liver and adult bone marrow. 
Multipotent stem cells in these tissues use an elab- 
orate gene program to generate millions of T and 
B lymphocyte clones, each expressing a T cell 
receptor (TCR) or Ig receptor of different antigen 
specificity. These are seeded via the bloodstream 
to the peripheral tissues, where they execute im- 
mune surveillance of foreign and self antigens. 
Inherited or acquired gene defects may specifi- 
cally alter growth or maturation of these cell 
lines to cause immune system dysfunction or 
malignancy. 
Comparative Analysis of T Cell Development 
We have embarked on a comparative analysis of 
T cell development in representative mamma- 
lian, avian, and amphibian species. Our studies in 
birds reveal remarkable evolutionary conserva- 
tion of the pattern of T cell development found in 
mammals, including the sequential development 
of cells bearing either the yh or a/3 TCR. 
Cells expressing the yb TCR are generated first 
during ontogeny. They may not undergo clonal 
selection during their intrathymic development. 
They migrate preferentially to splenic red pulp 
regions and the intestinal epithelium. Unlike afi 
T cells, the yb T cells cannot recognize class II 
molecules of the major histocompatibility 
(MHC) gene complex to initiate a graft-versus- 
host (GVH) attack. Analysis of their physiological 
role is facilitated by their relative abundance in 
birds (25-50 percent of T cells), where we are 
examining their development and functional 
capabilities. 
In collaboration with Craig Thompson (HHMI, 
University of Michigan) , we have used the TCR2 
and TCR3 antibodies to identify two discrete sub- 
lineages of a/3 cells that use different variable- 
region gene families: V/Sl and V|82. The avian V/Jl 
and V/32 genes contain highly conserved se- 
quences that distinguish the two major sub- 
groups of mammalian V/3 genes. Birds thus pro- 
vide a simple model system for study of the 
functional significance of these prototypic gene 
families. 
In birds, as in mammals, TCR/? diversity is cre- 
ated largely by nucleotide sequence variations in 
the joints between rearranged V/3, D (diversity), 
and J (joining) genes. Since V/51 and V|82 genes 
both combine with the same D and J genes, the 
V|S 1 ^ and V/32^ T cells should be capable of recog- 
nizing the same spectrum of antigenic peptides. 
However, the V/31 and Vj82 genes have little se- 
quence homology (less than 30 percent), so their 
protein products may interact differently with 
peptide-presenting MHC molecules. 
Indeed, although both V/31+ and V/32+ T cells 
can cause GVH disease in recipients with the 
same MHC class II genes, they do so with differ- 
ent efficiency. Selective inhibition of VjSl T cell 
development revealed that only the V;3l^ T cells 
can help B cells produce protective IgA antibod- 
ies along the mucous surfaces of the body. 
Current studies explore in more detail the func- 
tional capabilities of the VjSl and V(82 subpopula- 
tions of avian afi T cells. 
To analyze T cell development in an amphib- 
ian, we have made monoclonal antibodies that 
identify 7^ and a/3 TCR candidates expressed by 
separate lymphocyte subpopulations in Xenopus 
laevis. Frog T cells bearing the putative yb and 
TCR homologues exhibit the same tissue distri- 
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