T Lymphocyte Ontogeny and Specificity 
Michael J. Sevan, Ph.D. — Investigator 
Dr. Bevan is also Professor in the Department of Immunology at the University of Washington, Seattle. He 
received his Ph.D. degree for work performed at the National Institute of Medical Research, Mill Hill, Ion- 
don, England. He did his postdoctoral work at the Salk Institute in the laboratory of Melvin Cohn, after 
which he was Assistant and Associate Professor of Biology in the Center for Cancer Research and the De- 
partment of Biology at the Massachusetts Institute of Technology. He was a member of the Department of 
Immunology at the Research Institute of Scripps Clinic before moving to the University of Washington. 
Dr. Bevan was recently elected Fellow of the Royal Society. 
T lymphocytes mature in the thymus from 
bone marrow-derived hematopoietic stem 
cells. A key part of that process is the rearrange- 
ment of T cell receptor genes, the products of 
which will be expressed on the surface to recog- 
nize foreign antigens. The receptors, while 
highly varied, are expressed clonally: each T cell 
expresses only one kind of receptor. 
Two functionally different types of T lympho- 
cytes emerge from the thymus to populate the 
peripheral lymphoid organs. These are usually 
called helper and cytotoxic. In response to recog- 
nizing foreign antigen, helper T lymphocytes re- 
lease lymphokines, which augment the response 
of other lymphocytes, including B cells, to the 
antigen. Cytotoxic T lymphocytes specifically 
recognize cells that have become infected with 
intracellular pathogens and kill them efficiently. 
Although the same pool of receptor genes is 
used by both types of T lymphocytes, they are 
able to respond to quite different types of antigen 
by virtue of the different classes of MHC (major 
histocompatibility complex) molecules engaged 
in antigen presentation. The MHC encodes two 
types of surface glycoproteins: class I and class II. 
Killer cells recognize peptide components of for- 
eign proteins bound in the groove of class I MHC 
molecules, while helper cells recognize peptide 
antigens presented in the groove of class II 
molecules. 
Class I MHC glycoproteins are assembled with 
(82-microglobulin and a foreign peptide fragment 
shortly after synthesis in the endoplasmic reticu- 
lum. The peptides that become part of the class I 
complex are derived from intracellular self and 
foreign (viral) proteins. Class I MHC molecules 
do not associate with antigens that are taken up 
from the extracellular fluid. This is the world of 
class II presentation. Soluble extracellular anti- 
gens endocytosed by antigen-presenting cells are 
digested, then bound by class II molecules in en- 
dosomes. Because of this dichotomy in antigen 
presentation, the body mounts a helper T cell re- 
sponse to noninfectious extracellular antigens, 
and it mounts a cytotoxic T cell response to cells 
infected with viruses or bacteria. 
The generation of appropriate T cell receptors 
by gene rearrangement is not left to chance. Im- 
mature T cells expressing new receptors on their 
surface are only allowed to mature if the receptor 
has an appropriate affinity for class I or class II 
self MHC molecules. This process, referred to as 
"positive selection of the T cell receptor reper- 
toire," is quite stringent. Ninety percent of im- 
mature T cells expressing new T cell receptors 
fail this selection step and die in the thymus. 
Selecting the T Cell Repertoire 
T cells recognize fragments of foreign protein 
antigens bound in the groove of MHC-encoded 
molecules. The peptide-binding groove of the 
MHC molecule is extremely polymorphic, so that 
different alleles bind a different range of pep- 
tides. We know the crystal structure of a class I 
MHC molecule, and we have a good guess as to 
how peptide lies within it. Although we do not 
know the structure of the T cell receptor, a num- 
ber of groups have suggested that the receptor 
recognizes self MHC plus foreign peptide by con- 
tacting their residues on the face of the complex. 
Different alleles of MHC molecules expressed 
in the thymus select quite different T cells for 
maturation based on their receptor specificity. 
Since positive selection of the T cell repertoire is 
done in the absence of foreign peptides, it was 
commonly supposed that positive selection 
would be based on the affinity of the T cell recep- 
tor for the exposed outer faces of the MHC. We 
were able to show, however, by comparing the T 
cell receptor repertoire selected by variant class I 
molecules, that residue changes within the pep- 
tide-binding groove — i.e., not exposed on the 
outside of the molecule — determine the specific- 
ity of selection. The immediate interpretation is 
that the MHC class I groove is occupied by a self 
peptide during positive selection in the thymus, 
and the type of peptide is all important for the 
result. Our studies also suggest that a large variety 
of self peptides presented by the same class I mol- 
ecule select for different portions of the T cell 
repertoire. These unknown self peptides are 
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