DEVELOPMENT OF THE IMMUNE SYSTEM 
Max D. Cooper, M.D., Investigator 
Developmental biology of the immune system is 
the theme of Dr. Cooper's laboratory, in which dif- 
ferentiation of hematopoietic stem cells into immu- 
nocompetent T and B lymphocytes is explored. A 
major goal is to define abnormalities in these path- 
ways of cellular differentiation that lead to im- 
munodeficiencies and lymphoid malignancies. 
The accessibility of the avian embryo makes it a 
convenient model for developmental studies. The 
existence of separate T and B cell lineages with a 
common hematopoietic stem cell origin was eluci- 
dated through comparative studies of immune sys- 
tem development in chickens and mammals; this 
compartmentalization of the immune system is 
seen in all vertebrates. The genes encoding anti- 
body products of B cells are remarkably similar 
throughout the vertebrate kingdom, although di- 
vergent strategies exist for generating antibody di- 
versity. 
I. B Cell Development. 
B cells derived from a single IgM"*" precursor in 
bursal follicles were observed to produce a diverse 
spectrum of immunoglobulin light and heavy 
chains, which supports genetic evidence for so- 
matic diversification of the avian B cell repertoire. 
Epstein-Barr virus transformation of human pre- 
B cells was used to identify a novel cell type charac- 
terized by expression of immunoglobulin k or X. 
light chains without heavy chains. The heavy-chain 
(IgH) gene loci of K-only clones were in germline 
context or had undergone only D-J^^ rearrange- 
ment. This suggests the lOrchain protein is not an 
obligatory prerequisite for initiating light-chain 
gene rearrangement. 
Examination of the IgH gene configuration in a 
large panel of human B and T cell malignancies in- 
dicated that the recombinase activity involved in 
immunoglobulin isotype switching is primarily con- 
fined to B lymphocytes, often ineffective, and lacks 
isotype specificity. 
II. T Cell Development. 
Information on the T cell receptors and their en- 
coding genes is available for mammals, and recent 
studies in Dr. Cooper's laboratory indicate remark- 
able parallels in avian T cell development. Mono- 
clonal antibodies to chicken T cell antigens were 
used to trace the sequential development of T cells 
expressing "yS-like T cell receptors (TCRl) and of 
cells expressing a^-like T cell receptors (TCR2). 
Both the TCRl and TCR2 heterodimers reach the 
surface with a complex of CD3-like proteins. The 
subpopulations of avian T cells that express these 
receptors closely resemble their mammalian coun- 
terparts. 
The monoclonal antibodies against chick TCRl 
and TCR2 were the first TCR isotype-specific anti- 
bodies that could be used to identify native TCRl 
and TCR2 molecules on viable T cells. The experi- 
mental exploitation of these monoclonal antibodies 
revealed several interesting features of T cell devel- 
opment, especially regarding the enigmatic -y6 T 
cell. Developing as a separate sublineage, TCRl 
cells are generated before TCR2 cells. From the 
time they emerge in the embryonic thymus, TCRl 
cells express relatively high levels of their receptor 
complex, whereas TCR2 cells express gradually in- 
creasing levels of their surface receptors as they un- 
dergo maturation. The transit time of TCRl cells 
through the thymic cortex, into the medulla, and 
out to peripheral lymphoid tissues is several days 
less than that of TCR2 cells, and the homing pat- 
terns of the two are distinctive. TCRl cells migrate 
preferentially to splenic sinusoidal areas and intes- 
tinal epithelium, while TCR2 cells locate primarily 
in the splenic periarteriolar areas and intestinal 
lamina propria. In thymus and the circulation, most 
TCRl cells lack both the CD4 and CDS accessory 
molecules, but those in peripheral lymphoid tis- 
sues express CDS. This contrasts with the well- 
known pattern of CD4 and CDS expression by 
TCR2 thymocytes before they mature into CD4^ 
helper or CDS^ cytotoxic T cells. The TCRl sub- 
population is surprisingly large in birds, constitut- 
ing up to 50% of the adult T cell pool. This periph- 
eral pool of TCRl cells can be severely limited by 
early thymectomy, apparently because of a limited 
capability for population expansion. 
These observations indicate phylogenic conserva- 
tion of the TCRl subpopulation of cells. The pref- 
erential homing of the TCRl cells to splenic sinus- 
oids and intestinal epithelium places them in a 
strategic defense position. Their expression of CDS 
in these sites implies a cognitive kinship with 
cytotoxic TCR2 cells that utilize the CDS accessory 
molecule to reinforce their recognition of antigenic 
peptides present in the groove of major histocom- 
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