first such molecule that was shown to bind an endog- 
enous peptide and present it on the cell surface. In a 
collaboration with the laboratory of Dr. Michael Se- 
van, H-2M3 has now been shown to present a pep- 
tide derived from the intracellular parasite Listeria 
monocytogenes. Mice infected with Listeria make 
killer cells that recognize this peptide bound by 
H-2M3, which therefore plays a role in host defense 
against bacterial infection. Evidence has also been 
obtained that another medial class I antigen, Qa-l'', 
presents a minimum of four distinct, endogenous 
peptides. 
During a viral infection the immune system kills 
the virus and destroys infected cells. To do this it 
relies on one of the host's own proteins, HLA, to 
bind viral peptides, which are then recognized by T 
cells. Previous work used x-ray diffraction tech- 
niques to get a picture of HLA in atomic detail, and 
its structure suggested how it binds viral fragments 
and how T cells recognize it. Assistant Investigator 
Pamela J. Bjorkman, Ph.D. (California Institute of 
Technology) and her colleagues are now concen- 
trating on determining the structure of the T cell 
protein (the T cell receptor) that recognizes the 
peptide-HLA complex, and on studying the interac- 
tions between viral peptides and HLA molecules. 
In humans, HLA molecules, the cell surface pro- 
teins responsible for graft rejection, are critical for 
normal immune responses. In a phenomenon called 
antigen processing, they bind peptides derived from 
foreign organisms, allowing their recognition by 
immune T cells; the laboratory of Investigator Peter 
Cresswell, Ph.D. (Yale University) is studying this 
activity. Evidence has been obtained that a gene in 
the HLA complex is required for peptides to bind to 
the class II subset of HLA molecules. Other genes in 
the HLA complex are required for the intracellular 
transport of peptides that associate with class I HLA 
molecules. In the absence of the latter, peptides 
generated by a different mechanism, signal se- 
quence proteolysis, were found associated with cer- 
tain HLA molecules, revealing a new pathway of an- 
tigen processing. 
Associate Investigator David D. Chaplin, M.D., 
Ph.D. (Washington University) and his colleagues 
use yeast artificial chromosome (YAC) clones span- 
ning the human major histocompatibility complex 
(MHC) as reagents to define the complete gene con- 
tent of this important complex. Direct nucleic acid 
hybridization studies have identified a previously 
unrecognized gene that is expressed exclusively in 
dermal keratinocytes. Direct cDNA selection strate- 
gies have identified additional new HLA genes. 
Study of these genes may contribute to an under- 
standing of HLA-linked disease susceptibility. Other 
work by Dr. Chaplin concerns the immunomodula- 
tory cytokine interleukin-1 (IL-1). A novel cysteine 
protease, designated the IL-l/? convertase, is re- 
quired for activation of the isoform of this cyto- 
kine. The laboratory has defined the specificity of 
this protease and has cloned its cDNA. Current stud- 
ies suggest that the convertase is activated to cleave 
pro-IL-l;S as part of the programmed cell death 
pathway. Thus IL- 1 may either contribute directly in 
this pathway or may provide systemic signals regard- 
ing the occurrence of programmed cell death. 
The development of antibody-producing B cells 
from stem cells in the bone marrow has been a para- 
digm for studying molecular aspects of mammalian 
development. The research of Assistant Investigator 
Sankar Ghosh, Ph.D. (Yale University) and his col- 
leagues is focused on understanding the basis of reg- 
ulated expression of genes during B cell develop- 
ment. They anticipate that the knowledge gained 
will ultimately help to determine the causes under- 
lying aberrations that can occur in this developmen- 
tal pathway, e.g., B cell leukemia and lymphoma. 
The group is studying in detail how the NF-zcB pro- 
tein functions during B cell development in the pro- 
duction of antibodies. They are attempting to gener- 
ate transgenic mice where the normal activity of 
NE-/cB is altered, and they hope that such alterations 
will provide insight into how some malignant dis- 
orders of blood cells develop. 
Assistant Investigator Michel C. Nussenzweig, 
M.D., Ph.D. (Rockefeller University) and his col- 
leagues also study B lymphocytes. One important 
aspect of their development is the regulated assem- 
bly of a single antibody gene in each B cell. Allelic 
exclusion is the mechanism that insures unique 
clonal specificity in immune responses. Experi- 
ments with transgenic mice have shown that exclu- 
sion is regulated by a feedback signal from the 
membrane-anchored form of immunoglobulin pro- 
tein. Experiments currently under way are aimed at 
understanding the molecular nature of the feedback 
signal and how it affects allelic exclusion. 
The research in the laboratory of Associate Inves- 
tigator Craig B. Thompson, M.D. (University of Mich- 
igan) focuses on characterizing the molecular 
events associated with the regulation of lymphoid 
development and proliferation. Over the past sev- 
eral years the laboratory has made progress in defin- 
ing how genetic diversity is created in the immuno- 
globulin genes of developing avian B cells. This 
work has helped to provide insights into how ge- 
netic heterogeneity arises by the process of gene 
conversion. This group also continues to study gene 
IMMUNOLOGY 301 
