CHEMISTRY AND REGULATION OF EXPRESSION OF MAJOR HISTOCOMPATIBILITY 
COMPLEX-ENCODED CLASS I ANTIGENS 
Richard G. Cook, Ph.D., Associate Investigator 
The research in Dr. Cook's laboratory is focused 
on the biochemical structure, mechanisms respon- 
sible for tissue-specific regulation of expression, 
and function of class I cell surface antigens en- 
coded within the Q/TL region of the murine major 
histocompatibility complex (MHC). Approximately 
30 class I genes have been defined in the MHC, and 
more than 20 are localized to the Q/TL region, 
which is telomeric to the major transplantation an- 
tigen loci H-2KJDJL. Unlike the classical transplanta- 
tion antigens that bind foreign peptides and serve 
as restriction elements for the recognition of anti- 
gen by specific T cells, biological functions for the 
Qa and thymus leukemia (TL) class I antigens have, 
for the most part, remained elusive. All have been 
shown to serve as weak transplantation antigens, 
and several display a limited tissue distribution in 
comparison with the H-2K,D,L antigens. Although 
most of the class I genes lie within the Q/TL region, 
only a handful have been demonstrated to encode 
the serologically defined products that reside in 
this region. It is likely that the Qa and TL antigens 
also bind foreign and self peptides and thus func- 
tion in a manner similar to H-2K,D,L, but there is 
little evidence for this. Recent data suggest that the 
novel ^S-receptor T cells may recognize or be re- 
stricted to antigens encoded within the Q/TL re- 
gion. Thus these molecules may subserve a specific 
and special function in immune recognition and 
surveillance. Several of the class I genes in this re- 
gion are thought to be nonfunctional pseudogenes, 
whereas others may be functional and encode 
products that have eluded detection. Dr. Cook and 
his colleagues are investigating the function, struc- 
ture, and regulation of expression of the Qa-2 anti- 
gen family, the Qa-1 and TL alloantigens. 
I. TL Region-Encoded TL Antigen. 
Although 13-18 class I genes are within the TL 
region, only one serologically and biochemically de- 
fined product, TL, has been correlated with a spe- 
cific gene. The T13 gene has been shown to encode 
a TL antigen in the BALB/c strain. Several of the 
other TL genes are pseudogenes; others appear to 
be functional and may encode products that have 
not yet been defined. 
TL displays a more restricted tissue distribution 
than other class I antigens. It is expressed on thy- 
mocytes, certain leukemia cell lines, and activated 
peripheral T lymphocytes. Other tissues, including 
resting peripheral T cells, B cells, and macro- 
phages, are negative. Recent data from another lab- 
oratory indicate that a TL-like molecule and the T13 
gene product are expressed in fetal liver cells. Be- 
cause of this distinctive regulation of TL expression. 
Dr. Cook and his colleagues are attempting to char- 
acterize the molecular genetic controls responsible 
for TL gene expression and activation. Previous data 
have shown that the TL message is detected in thy- 
mocytes and activated T cells but not in resting pe- 
ripheral T cells; this agrees with the serological and 
biochemical studies. For thymocytes from any given 
TL haplotype, there were 2-3 TL mRNA species 
differing in size. In contrast, TL transcripts from ac- 
tivated T cells were less heterogeneous and repre- 
sented a subset of the transcripts seen in thy- 
mocytes. Thus activated T cells may express fewer 
TL genes or may contain fewer aberrant transcripts. 
The 5 '-upstream region of the T13 gene is being an- 
alyzed for enhancer elements that may be impor- 
tant for the novel cell lineage and activation-state 
expression of the TL. Various 5' segments fused 
to the reporter gene chloramphenicol acetyltrans- 
ferase (CAT) have been electroporated into several 
cell lines and tested for CAT activity. Preliminary 
data indicate that there are enhancer elements 
within the T13 upstream region that seem to func- 
tion in a tissue- and cell-specific manner. Experi- 
ments to define more precisely these enhancer 
motifs and the nuclear factors responsible for regu- 
lated expression of TL are in progress. 
II. Murine Qa-2 Antigen Family. 
An additional Q/TL region molecule being exam- 
ined in this laboratory is the Qa-2 antigen family. 
Cell surface forms of the prototype Qa-2 antigen 
(which was presumed to be nonpolymorphic) and 
the Qa-6 antigen are indistinguishable by biochemi- 
cal techniques; however, based on analysis of re- 
combinant mouse strains, Qa-6 is encoded or con- 
trolled by a gene distinct from the Qa-2 gene. The 
Qa-6 determinant does not appear to result from a 
modification of the Qa-2 antigen. 
Dr. Cook's laboratory has correlated the expres- 
sion of Qa-6 with a distinct Qa-2 -associated poly- 
peptide found in Qa-2"^6^ but not Qa-2"^6" strains. 
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