MOLECULAR ASPECTS OF DIFFERENTIATION AND PROLIFERATION OF THE LYMPHOID SYSTEM 
Craig B. Thompson, M.D., Assistant Investigator 
Dr. Thompson's research is focused on the mo- 
lecular events associated with cellular differentia- 
tion and proliferation of the immune system. Over 
the preceding year the laboratory has concentrated 
on two major projects: 1) characterizing B cell de- 
velopment in the avian bursa of Fabricius and 2) 
defining molecular mechanisms involved in regulat- 
ing gene expression during the activation of normal 
human T cells. 
I. Bursa of Fabricius as a Model System for the 
Study of Lymphoid Development. 
The bursa of Fabricius provides a unique organ 
for understanding lineage-specific development in a 
multicellular organism. B cells in the chicken, un- 
like in mammals, develop in a single wave of differ- 
entiation, beginning with commitment of progeni- 
tor cells to B cell differentiation between days 10 
and 15 of embryogenesis. By day 18 of embryogen- 
esis, all lymphoid progenitor cells capable of differ- 
entiation along the B cell lineage have migrated to 
the bursa of Fabricius. After migration to the bursa, 
these lymphoid progenitors enter exponential 
growth and begin to populate each of the lO'^ bur- 
sal follicles. Between day 18 of embryogenesis and 
2-4 weeks of age, B cells undergo a stage of bursal- 
dependent differentiation. By the end of this pe- 
riod, chickens are able to mount primary immune 
responses against virtually all antigens. In addition, 
by 4 weeks of age sufficient numbers of B cells have 
migrated from the bursa to peripheral lymphoid or- 
gans so that the B cell immune system can be main- 
tained, even if the bird is bursectomized. Bursecto- 
my of chicks after 4 weeks of age has no long-term 
effect on the development and maintenance of the 
B cell immune system in adult birds. 
Because of the central nature of the surface Ig 
molecule to B cell development in mammals. Dr. 
Thompson and his colleagues have undertaken a 
characterization of the chicken Ig light-chain (Ig^^) 
locus during bursal development. Several years ago, 
this locus was shown to have only one V region ca- 
pable of rearrangement. To create an immunologi- 
cal repertoire, chickens must diversify the coding 
sequence of this functional V gene segment at some 
point during development. This diversification oc- 
curs subsequent to Ig^^ rearrangement during the 
bursal-dependent phase of B cell development. Ig^^ 
gene diversification is limited to the rearranged V 
gene segment and occurs by a gene conversion 
mechanism, using V region pseudogenes as se- 
quence donors. In contrast to diversification, rear- 
rangement of the Igj^ gene is not dependent on the 
bursal environment. B cell progenitors rearrange 
their Ig^^ gene between days 10 and 15 of embryo- 
genesis, prior to migration to the bursa. gene re- 
arrangement occurs by a deletional mechanism in 
which a precise joining of the Igj^ recombination 
signal sequences leads to a circular episomal ele- 
ment. During this deletion it appears that single 
nonrandom bases are added to both the V and J 
coding segments. Subsequent V-J joining appears to 
occur at random. Most progenitor B cells appear to 
rearrange only a single Ig^^ allele. The high fre- 
quency of in-frame alleles observed in avian B cell 
lines appears to result from the selective amplifica- 
tion of cells with productive Ig^^ rearrangements 
during bursal development, between days 12 and 
18 of embryogenesis. The continued characteriza- 
tion of B cell differentiation within the bursa of 
Fabricius remains a central focus of Dr. Thompson's 
laboratory. 
II. Normal Human T Cells as a Model System for 
the Study of Gene Expression During Cellular 
Activation. 
Nuclear proto-oncogenes have been character- 
ized as having a potential role in the regulation of 
cellular proliferation. This has led to an expanded 
interest in the molecular events associated with the 
transition of a lymphocyte from a quiescent state to 
one of either cellular proliferation or effector func- 
tion. To study these events in a normal quiescent 
cell population. Dr. Thompson and his colleagues 
have concentrated on characterizing molecular events 
associated with human T cell activation. Although 
many other laboratories have a similar interest, Dr. 
Thompson's laboratory is using defined purified 
populations of normal resting human T cells isolat- 
ed by lymphopheresis and negative selection using 
monoclonal antibodies. The laboratory has concen- 
trated on how molecular events transduced through 
the T cell receptor and accessory T cell surface mol- 
ecules regulate the expression of a variety of genes 
associated with cellular proliferation and T cell 
function. These genes have included the nuclear 
proto-oncogenes, lymphokine genes, T cell recep- 
tor genes, and activational T cell surface markers. 
Continued 
445 
