munodeficiency syndrome. The laboratory also stud- 
ies steps that convert latent human immunodefi- 
ciency viral infection to active disease. They have 
found signals that activate viral replication and have 
elucidated the mechanism of hov^^ one viral protein 
augments these cellular responses. In particular, the 
Tat protein was found to affect replication of HIV by 
a new transcriptional mechanism. 
Thymus-derived lymphocytes or T cells are an im- 
portant part of the body's defense against microor- 
ganisms. They also are thought to mediate disease 
development in certain autoimmune diseases and to 
operate in organ transplant rejection. To understand 
better how T cells develop under normal circum- 
stances, genes important in T cell function have 
been cloned and reintroduced into transgenic mice 
in the laboratory of Associate Investigator Dennis 
Y.-D. Loh, M.D. (Washington University). Results in- 
dicate how T cells learn to discriminate self and 
non-self markers to maintain the balance of the 
body's immune system. 
T cells recognize the appearance of infections in 
the body and orchestrate their destruction. In doing 
this, however, it is essential that T cells do not recog- 
nize and turn on the tissues of their own host. Many 
potentially autoreactive T cells die while they are 
developing in the thymus. Recent experiments by 
Investigator Philippa Marrack, Ph.D. (National Jew- 
ish Center for Immunology and Respiratory Medi- 
cine) and her colleagues show that other such cells 
die after they have matured when they encounter 
self elsewhere in the animal. This type of event may 
affect not only the ability of T cells to destroy their 
host but also the ability of T cells to attack chronic 
infections such as herpes or Epstein-Barr virus. 
Although T cells of the immune system usually 
play a critical role in the resistance to microbial in- 
fection, some microorganisms produce a superanti- 
gen, whose ability to overstimulate T cells helps the 
pathogen rather than the host. Well-known exam- 
ples of these proteins are a number of the toxins 
produced by staphylococcal bacteria, whose activa- 
tion of very large numbers of T cells can cause the 
symptoms of food poisoning and toxic shock. These 
superantigens are under study by Investigator John 
W. Kappler, Ph.D. (National Jewish Center for Im- 
munology and Respiratory Medicine) and his col- 
leagues. With an understanding of how these pro- 
teins interact with the immune system has come the 
realization that they are much more widespread in 
the microbial world of bacteria, viruses, and myco- 
plasma than originally thought. Their disruption of 
the immune system not only causes obvious acute 
symptoms but also may have more subtle long- 
lasting effects, possibly setting in motion the mecha- 
nisms of autoimmunity. 
Mechanisms of immunological unresponsiveness 
remain of fundamental interest in understanding the 
regulation of immune responses. Patients with le- 
promatous leprosy are immunologically unrespon- 
sive to antigens of Mycobacterium leprae and un- 
able to control their infection. Studies in the 
laboratory of Investigator Barry R. Bloom, Ph.D. (Al- 
bert Einstein College of Medicine) of the lympho- 
cytes from lesions of this disease and the lympho- 
kines they produce revealed that a subset of T cells, 
expressing the CDS surface marker and producing 
interleukin-4, is responsible for suppressing re- 
sponses of potentially protective T cells. The related 
mycobacterium, M. tuberculosis, was found to be 
highly resistant to usual mechanisms of protective 
killing used by macrophages but uniquely suscepti- 
ble to reactive nitrogen intermediates, particularly 
nitric oxide. The study of these infectious diseases is 
providing insights into basic mechanisms of immu- 
nological tolerance and resistance. 
The laboratory of Assistant Investigator William R. 
Jacobs, Jr., Ph.D. (Albert Einstein College of Medi- 
cine) has developed the tools to manipulate geneti- 
cally the slow-growing mycobacteria M. tuberculo- 
sis and the tuberculosis vaccine, BCG (bacille 
Calmette-Guerin) . By using genetic approaches, it is 
hoped that significant insights will be gained in un- 
derstanding the biology of M. tuberculosis infec- 
tions that will be important in developing novel 
therapies to control this dreaded disease. Another 
facet of the research involves the cloning of foreign 
antigens from parasitic pathogens, such as Leish- 
mania or Schistosoma, into BCG in order to gener- 
ate recombinant vaccines that might protect against 
tuberculosis and the pathogen from which the for- 
eign gene is derived. 
Cytotoxic T lymphocytes recognize and kill cells 
that express foreign antigens on their surface. Anti- 
gen is presented in the form of short peptide frag- 
ments bound to the class I major histocompatibility 
complex molecules. The laboratory of Investigator 
Michael J. Bevan, Ph.D. (University of Washington) 
has been interested in one class I molecule that is 
specialized to bind and present bacterial peptides to 
cytotoxic T cells. The class I binding site recognizes 
the TV-formylmethionine residue that initiates all 
bacterial polypeptides. 
Investigator Kirsten Fischer Lindahl, Ph.D. (Uni- 
versity of Texas Southwestern Medical Center at 
Dallas) and her colleagues study the function of the 
nonclassical or medial class I antigens of the mouse 
major histocompatibility complex. H-2M3 was the 
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