IMMUNODOMINANCE IS INDEPENDENT OF STRUCTURAL CONSTRAINTS - EACH REGION WITHIN HEN EGG-WHITE LYSOZYME IS POTENTIALLY AVAILABLE UPON PROCESSING OF NATIVE ANTIGEN
Kd. Moudgil et al., IMMUNODOMINANCE IS INDEPENDENT OF STRUCTURAL CONSTRAINTS - EACH REGION WITHIN HEN EGG-WHITE LYSOZYME IS POTENTIALLY AVAILABLE UPON PROCESSING OF NATIVE ANTIGEN, The Journal of immunology, 159(6), 1997, pp. 2574-2579
Upon challenge with native Ag and later recalling the response in vitr
o using synthetic peptides, the responses to different T cell determin
ants can be categorized as dominant, subdominant, or cryptic (1). It h
as been reported in different experimental systems that T cell respons
es to a protein Ag (e.g., hen eggwhite lysozyme (HEL),(3) cytochrome c
, OVA, sperm whale myoglobin, staphylococcal nuclease, lambda represso
r, influenza virus hemagglutinin, and ragweed allergen) are focused on
to a few determinants, termed the ''immunodominant'' determinants (2-1
2). A variety of explanations have been proposed to explain immunodomi
nance of certain determinants over others within an Ag (reviewed in Re
fs. 1, 4, and 8), for example: 1) special structural properties intrin
sic to certain regions of an Ag (reviewed in Ref. 8); 2) efficient pro
cessing of these determinants from native Ag (relative availability) (
13, 14); 3) better binding of certain determinants to a particular MHC
molecule (15, 16); 4) promiscuous binding of a peptide to different M
HC molecules (17, 18); 5) competition between determinants for binding
to the same or different MHC (4, 19-21); 6) the number of MHC/peptide
complexes presented on the surface of the APC as well as their stabil
ity (22), which is a function of several of the above; 7) the proofrea
ding action of nonclassical class II, H-2 M/DM, which favors presentat
ion of long-lived MHC class II/peptide complexes to T cells (23, 24);
and 8) a higher frequency of T cells potentially reactive to the immun
odominant determinant in the mature T cell repertoire (4, 8, 10, 25),
etc. In this study, we have addressed three important questions regard
ing immunodominance using HEL as a model Ag: first, are only certain r
egions within HEL revealed as immunodominant, while other areas within
the molecule are either rarely, if ever, utilized or never become rev
ealed upon challenge with HEL, owing to structural constraints? Second
, is the response to HEL of congenic, MHC-disparate mouse strains with
identical non-MHC genes restricted to one or more members of a set of
determinants as a result of any processing constraints imposed by the
background genes? Third, how different is the pattern of immunodomina
nce of determinants within HEL in mice having a truncated TCR repertoi
re compared with wild-type mice? Our results from 19 strains of mice w
ith 11 different MHC haplotypes suggest that each contiguous region of
HEL has the potential to be immunodominant, and thereby immunodominan
ce or immunorecessiveness is not structurally favored or constrained,
respectively, by the primary or secondary structure of the Ag. Further
more, even under apparently similar Ag-processing conditions, the immu
nodominant determinants of HEL responded to by various mouse strains a
re distributed all over the molecule; however, the identity of determi
nants displayed by different strains is primarily determined by the MH
C of the host. Finally, our results show that mice having a truncated
TCR repertoire can sometimes lose response to certain immunodominant d
eterminants of HEL, but apparently their ability to raise a response t
o native HEL is not seriously compromised.