Molecular Mechanisms That Regulate B Cell Development 
peptide, is not required for transport or signal 
transduction. Progress in understanding the func- 
tional role of the immunoglobulin receptor sub- 
units in signaling has been hindered by the multi- 
subunit nature of the receptor. In addition, 
transfected immunoglobulin expressed on the 
surface of fibroblasts does not appear to be func- 
tional for signal transduction, even in the pres- 
ence of B29 and MBl. Our ability to produce a 
functional receptor by transfection in T cells es- 
tablishes that there is enough structural similarity 
between the T and B cell signal transduction 
pathways to allow recognition of the IgM-B29 
complex in T cells. This observation should sim- 
plify the structural and functional analysis of 
the IgM antigen receptor and ultimately allow 
us to understand how membrane immunoglobu- 
lin signals for antigen recognition and allelic 
exclusion. 
In addition to our ability to study the structural 
requirements for immunoglobulin function, our 
experiments also have potential clinical implica- 
tions. One major difference between the T cell 
receptor and immunoglobulin antigen receptors 
is the nature of the antigen recognized. Immuno- 
globulins recognize antigens directly; the major 
histocompatibility complex (MHC) restricts rec- 
ognition of antigen by the T cell receptor. The 
requirement for MHC recognition severely limits 
the targets recognized by T cells and restricts 
transfer of cellular immunity. Our reconstitution 
experiments offer one potential solution to this 
difficult clinical problem — the production of T 
cells that utilize immunoglobulins as antigen re- 
ceptors. In T cells that recognize antigen with 
immunoglobulin receptors there is no MHC re- 
striction, and thus this barrier to transfer of cellu- 
lar immunity is potentially abrogated. 
Our second goal has been to understand allelic 
exclusion at the genetic level. We have docu- 
mented that chromosomal position plays an im- 
portant role in the regulation of gene rearrange- 
ments in the immunoglobulin locus. In addition 
we have started to investigate the regulatory 
function of the recombinase genes RAG-1 and 
RAG-2 in allelic exclusion. Deregulating the ex- 
pression of the RAG genes in the lymphocytes of 
transgenic mice has profound effects on lympho- 
cyte differentiation and function. Animals that 
carry /MG- 1 and /2/4G'-2transgenes develop hepa- 
tosplenomegaly and a profound lymphoprolif- 
erative disorder that is rapidly lethal. We are 
pursuing a molecular understanding of the patho- 
genesis of this disorder. 
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