T Lymphocyte Biology and Genetics 
Robert R. Rich, M.D. — Investigator 
Dr. Rich is also Professor of Microbiology and Immunology and of Medicine at Baylor College of Medicine 
and Attending Physician at Baylor College of Medicine and affiliated hospitals. He received his under- 
graduate education at Oberlin College and his M.D. degree from the University of Kansas. After a residency 
in internal medicine at the University of Washington, he had postdoctoral fellowships at the NIH with 
Sheldon Wolff and Charles Kirkpatrick and at Harvard Medical School with Baruj Benacerraf and Carl 
Pierce. 
MULTICELLULAR organisms have evolved 
complex mechanisms to differentiate them- 
selves from their environments and to perceive 
and defend against potential threats to their in- 
tegrity. The immune system of vertebrates is a 
sophisticated defense system organized to deal 
with attack at the microbial and/or molecular 
level. Recent data indicate that microbial organ- 
isms similarly have evolved mechanisms to en- 
hance the effectiveness of their interactions with 
specific recognition elements of vertebrate im- 
mune systems. The primary focus of specific rec- 
ognition by the immune system is a specialized 
subpopulation of lymphocytes, termed T cells, 
that is responsible for discriminating molecules 
perceived as self from those that are foreign. Sev- 
eral families of genes are directly involved in this 
process, including genes that encode the T cell 
receptor for antigen and those of the major histo- 
compatibility complex (MHC). 
The MHC genes, which exist as a linked cluster 
on a single chromosome, are intimately involved 
in the definition of "self" for cells of the immune 
system. The importance of the MHC in self- 
nonself discrimination was appreciated long be- 
fore its essential role in antigen recognition was 
defined. As suggested by its name, the MHC con- 
stitutes the major barrier to exchange of tissue 
grafts between members of a vertebrate species. 
T cell receptors recognize foreign antigen 
solely in the context of self MHC molecules, 
which are expressed on the surfaces of cells spe- 
cialized for antigen presentation. Recent data 
suggest that recognition is accomplished by the 
specific binding of small peptide antigens within 
a groove on the outer face of MHC molecules. T 
cell receptors are thought to be selected during 
differentiation in the thymus for their capacity to 
bind this binary complex of foreign peptide and 
self MHC. 
Our objectives include definition of the genes 
and gene products of the MHC in mice and hu- 
mans and incorporation of such information into 
an understanding of T cell recognition of foreign- 
ness. The relationships between the structure of 
MHC molecules and their biological functions 
are of particular interest. Two major classes of 
MHC molecules have been defined by their dis- 
tinctive structural features. Molecules of 
both classes are important in self-nonself 
discrimination. 
T cells involved in induction of immune re- 
sponses primarily employ class II MHC mole- 
cules. Three major types of human class II mole- 
cules are recognized: DP, DQ, and DR. Previously 
we employed cloned T cells to define the contri- 
butions of each type to the recognition of foreign 
antigens and to investigate the cellular mecha- 
nisms involved in antigen presentation. A DR mol- 
ecule was identified with unique biochemical 
features and distinctive defects in its capacity to 
function in antigen presentation. This defect was 
highly associated with a deficiency in activity of 
linked genes controlling an enzyme important in 
the biosynthesis of adrenal steroids. Because an 
understanding of the DR molecule should pro- 
vide insight into general structure-function rela- 
tionships of MHC molecules, we sequenced 
cDNAs encoding its constituent polypeptides. 
The biochemical and functional anomalies were 
associated with point mutations in two adjacent 
codons, resulting in amino acid substitutions 
within the ;8-chain of the DR molecule. These 
substitutions are hypothesized to affect interac- 
tions between the ^- and a-chain polypeptides 
and may affect binding of foreign antigenic pep- 
tides. Studies in progress are designed to eluci- 
date the molecular mechanisms accounting for 
the unique properties of this molecule. 
Our studies of MHC class Il-dependent T cell 
stimulation led us to analysis of the mitogenic 
activities of a family of staphylococcal exotoxins 
that have been of considerable medical interest as 
the etiologic agents of staphylococcal food poi- 
soning and toxic shock syndrome. The recent ap- 
preciation of unique aspects of the interaction of 
these bacterial products with T cell receptors, 
and their capacity to thus shape the T cell reper- 
toire, has led to their designation as "superanti- 
gens" (Philippa Marrack [HHMI] and John 
Kappler [HHMI], National Jewish Center for Im- 
munology and Respiratory Medicine, Denver). 
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