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Department of Microbiology and Molecular Genetics, University of California, Los Angeles, CA 90095
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Of these, a major hurdle for a particular determinant to be presented efficiently to the TCR is the competition among different regions within the native Ag for binding to ambient class II MHC molecules (1, 2, 12, 13), and among different MHC molecules for binding to the "prodeterminant" (1) bearing many determinants. Accordingly, the interplay of various factors outlined above and the final outcome of the immune response to determinants of an Ag is expected to be much more complex in a hybrid F1 individual carrying each of the parental MHC molecules as well as hybrid MHC molecules (14, 15) in comparison to the inbred parental strains. Nevertheless, it is generally believed that with regard to the immune response to a foreign/self Ag, F1 mice derived from established inbred parental mouse strains behave in a consistent, reproducible fashion, like a new inbred strain. Hybrid F1 mice have extensively been used in immunologic studies in animal models of human autoimmune diseases [e.g., systemic lupus erythematosus (SLE), experimental autoimmune encephalomyelitis (EAE), experimental autoimmune uveoretinitis (EAU), experimental autoimmune pinealitis (EAP), etc. (16, 17)] and in tissue/organ transplantation (18).
In this report, we describe the patterns of immunodominance of determinants within hen eggwhite lysozyme (HEL)3 in five well-defined, inbred parental strains and three different hybrid F1 strains derived from them. We observed that in comparison to parental strains, individual members of F1 strains [(B6 x BALB/c)F1, (B6 x CBA/J)F1, and (SJL x B10.PL)F1] responded to HEL in a significantly heterogeneous manner, which involved changes in responsiveness to the major, dominant determinants. We attribute this heterogeneity to a degree of chaotic behavior owing to the abundance of different MHC molecules and background gene products in the F1 animal. This study provides a novel, antigenic determinant-specific perspective on the heterogeneity of individual F1 mice. These results have important implications for human immunology.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c (H-2d), B10.PL (H-2u), C57BL/6 (=B6) (H-2b), SJL (H-2s), and CBA/J (H-2k) mice were either purchased from The Jackson Laboratory (Bar Harbor, ME) or bred in our animal facility. F1 mice, namely (B6 x BALB/c)F1, (B6 x CBA/J)F1, and (SJL x B10.PL)F1, were bred from the above-mentioned parental strains. Mice of either sex, 6–20 wk of age, were used.
HEL, and peptide synthesis and purification
HEL was purchased from Sigma (St. Louis, MO) and further purified as described (13). HEL peptides were obtained from the following sources: a) Overlapping 15-mer HEL peptides were obtained from Chiron Mimotopes (San Diego, CA). These peptides were synthesized using the "multipin" peptide synthesis technique (19). The terminal amino group of each peptide was acetylated, whereas the carboxyl-terminal lysine-proline residues transformed into diketopiperazine. b) Some peptides were synthesized in our laboratory using the rapid simultaneous solid-phase multiple-peptide synthesis methodology, the so-called "teabag" method (20, 21). c) Some peptides were obtained from Macromolecular Resources (Colorado State University, Fort Collins, CO) (21), whereas others were synthesized in the UCLA Peptide Core Laboratory using a Multiple Peptide Synthesizer (Advanced Chem Tech, Louisville, KY) (7). The identity and purity of these peptides were determined by fast atom bombardment mass spectrometry.
Lymph node proliferation assay
Mice were immunized with 7 nmol/mouse of HEL or a HEL peptide in
PBS, in 1:1 (v/v) emulsion with CFA (Difco Laboratories, Detroit, MI),
in a hind foot pad. After 9 days, the draining lymph nodes were
removed, cell suspensions washed twice with HBSS (Life Technologies,
Grand Island, NY), and then cultured in a flat-bottom 96-well plate at
a concentration of 5 x 105 cells/well in X-Vivo-10
serum-free medium (BioWhittaker, Walkersville, MD) using different
concentrations (1.66–20 µM or higher, final concentration) of the
Ag. Tuberculin purified protein derivative (Parke-Davis, Morris Plains,
NJ) was used at a final concentration of 4 µg/well as a positive
control. The cells were incubated with 1 µCi/well of
[3H]thymidine (International Chemical and Nuclear,
Irvine, CA) for the last 18 h of a 5-day culture. The cells were
then harvested using a Micro Cell Harvester (Skatron Instruments,
Sterling, VA), and the incorporation of radioactivity
was assayed by liquid scintillation counting using the LKB 1205
Betaplate counter (LKB-Wallac, Gaithersburg, MD). For some
repeat experiments, X-Vivo-10 medium supplemented with 5 x
10-5 M 2-ME was used. The results of these experiments
were comparable to those of earlier, similar experiments in which
X-Vivo-10 medium without 2-ME supplementation was used. The results
were expressed as mean cpm of duplicate or triplicate cultures. For
presentation of data, background values of cpm [cpm of lymph node
cells (LNC) cultured in medium without Ag] were subtracted from the
cpm obtained with LNC plus Ag (
cpm). Alternatively, the value of
cpm with Ag was divided by the cpm with medium alone [stimulation
index (SI)]. Ag doses of 10–20 µM covered the optimum concentration
for proliferative response of all the HEL peptides tested. The final
results from a group of animals immunized with the same peptide were
expressed either as mean cpm (or cpm) ± SD or mean SI ± SD.
Based on the value of average SI obtained with the optimal
concentration of the peptide, the response to each peptide was
arbitrarily graded as follows (21): SI of <3, -; 3–3.9, ± ; 4–9.9,
+; 10–24.9, 2+; 25–49.9, 3+; and 50–100, 4+.
Grading of pattern of responses to HEL of individual parental/hybrid F1 mice
The patterns of response to HEL of individual members of parental strains were analyzed, and mice with similar patterns of response were grouped together. For comparison with F1 mice, an average pattern of response of all members of a particular parental strain was derived from the average response (average SI) to each peptide of HEL. Classification of patterns of response to HEL of F1 mice into different groups was done as follows: A, preference toward one parent; B, preference toward the other parent; A- (or B-), preference toward one parent but loss of one or more determinant(s) (e.g., A-1, A-3); A+ (or B+), preference toward one parent along with gain of one or more new determinant(s) (e.g., A+1, A+2); A-,+ (or B-,+), a basic pattern like parent A but with loss of response to one or more determinant while concurrently gaining a response to one or more new determinants (e.g., A-1,+2); AB, response to determinants of both parents, the response profile varying from a full spectrum comprised of all determinants responded to by the two parental strains to a partial spectrum represented by only certain parental determinants. For example, group A-2,+1B+1 represents a pattern of response consisting of determinants responded to by the two parents, but in comparison to parent A, there is a loss of two determinants but a gain of a new determinant, whereas in comparison to parent B, there is a gain of a new determinant; C, loss of response to all determinants of both parents, but a positive response to native HEL and purified protein derivative. To determine the representative "whole group pattern," the mean SI of all F1 mice in that group for each of the HEL peptides tested was calculated separately, and the average response profile was assigned the appropriate category.
Statistical analysis
As a measure of homogeneity of a population with respect to a
particular trait, we used H to represent the sum of squares of the
population proportions. The value of H was computed from the observed
number of population trait patterns (i.e, number of different patterns
of response to HEL of a given mouse strain), and the observed
proportion of members of that population with a particular trait
pattern (i.e., the proportion of mice of that strain giving an
identical pattern of responses). H has values from zero to one (0
H 1), with a large value of H indicating a more homogeneous
population, and a small value indicating a more heterogeneous
population. To compare the homogeneity of response to HEL of parental
vs F1 mouse strains, we employed a nonparametric,
two-sample permutation (randomization) test based on hypergeometric
distribution. We first determined the number of mice in each category
that gave a similar pattern of response. This information was then used
to determine whether parental strains differ significantly from the
respective F1 strains in regard to consistency of the
patterns of response. The statistical significance of the final result
was assessed from the p value.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Response to HEL of the parental mouse strains
The response of individual mice of five of the parental strains to HEL is shown in Tables I and II. Interestingly, the pattern of responses of parental strains that responded to only a few (one to three) HEL determinants (e.g., B6, BALB/c, and B10.PL) were quite consistent. On the other hand, mouse strains that responded to multiple determinants of HEL revealed either relative homogeneity (CBA/J) or heterogeneity (SJL) of response. Nevertheless, in the SJL strain, responses to major, dominant determinants of HEL were quite consistent. The above conclusions regarding the consistency of response patterns were supported by the results of statistical analyses (see Tables I and II).
Immunodominance of T cell determinants of HEL in hybrid F1 mice
The T cell responses of HEL/CFA-immunized (B6 x
BALB/c)F1 are given in Table III
. Strikingly, although B6 and BALB/c
parents showed a high consistency of responses to HEL (Table I),
individual (B6 x BALB/c)F1 mice revealed six
different types of patterns (Table III). Interestingly, despite this
heterogeneity, a majority (20 of 24; 83%) of F1 mice
responded to determinant 106–116, which represents the sole
immunodominant determinant in BALB/c mice ("determinant-specific"
bias). In 14 of 24 (58%) F1 mice, there was a loss of
response to all the B6-specific determinants, 20–35, 30–53, and
74–96 (pattern B), whereas 6 of 24 (25%) of F1 mice had
patterns (e.g., A-2,+1B+1, and
A-2,+2B+2) including certain determinants from
both parents. The overall pattern of the average response of the whole
group of F1 mice (pattern B) to various HEL determinants
was found to be similar to that of BALB/c mice
("haplotype-specific" bias).
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). Surprisingly, an entirely opposite
pattern of response was observed in these F1 mice regarding
two determinants of HEL, 20–35 and 30–53, which are responded to by
both parental strains: 17 of 21 (81%) of F1 mice responded
to p20–35, while 18 of 21 (89%) of F1 mice lost responsiveness
to p30–53.
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Nevertheless, on one hand, 32 of 35 (91%) F1 mice
responded to HEL p30–53 (a B10.PL determinant)
("determinant-specific bias"), while on the other hand, responses
to at least three determinants of HEL that represent the immunodominant
determinants for the SJL strain (namely 20–35, 74–96, and 116–129)
were significantly decreased or almost lost in (SJL x
B10.PL)F1 mice!
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Hybrid F1 mice fail to respond to certain HEL determinants despite possessing the appropriate T cell repertoire
We have described above that in each of the three strains of
F1 mice studied, many individual mice immunized with native
HEL did not raise a proliferative response to certain dominant HEL
determinants to which one or both parents responded strongly (Tables
III-V). To determine whether these F1 mice possessed the
requisite T cell repertoire potentially directed against a particular
HEL determinant (but yet could not raise a response to that determinant
after challenge with native HEL), we immunized F1 mice with
a HEL peptide (instead of native HEL), and then tested the draining LNC
in a proliferation assay using the same peptide for a recall response.
Another batch of F1 mice was immunized with native HEL and
then tested for recall response to HEL peptide. The results are given
in Table VI. Strikingly, mice of each of
three F1 strains tested raised a vigorous recall response
to the HEL peptide tested following peptide immunization. On the
contrary, each of these F1 strains failed to give a recall
response to the same HEL peptide following immunization with native
HEL. These results demonstrate that the failure of some F1
mice to respond to certain determinants of HEL was not owing to
particular holes in the T cell repertoire; instead, it was attributable
to failure of processing and/or presentation of that determinant from
native HEL by F1 APC. Interestingly, in some but not other
individuals of (B6 x BALB/c)F1 and (B6 x
CBA/J)F1 mice immunized with HEL peptide 30–53, response
to this peptide could also be recalled with native HEL. These mice
represent those F1 members that had the potential to
respond to this determinant upon challenge with native HEL.
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To further define the mechanism of loss of response to HEL
determinant 30–53 in a majority of (B6 x CBA/J)F1
mice, we tested the response to HEL peptide 30–53 in [B10.A(4R) x
CBA/J]F1 mice immunized with HEL. We reasoned that
(B6 x CBA/J)F1 and [B10.A(4R) x
CBA/J]F1 mice have nearly identical non-MHC background
genes but differ in their MHC composition: [H-2b
(Ab) x H-2k (Ak, Ek)]
and [H-2h4 (Ak) x H-2k
(Ak, Ek), respectively]. Thus, if responses to
determinant 30–53 were lost readily in (B6 x
CBA/J)F1 mice but not in [B10.A(4R) x
CBA/J]F1 mice following challenge with native HEL, it
could possibly be attributable to the presence of the Ab
molecule ("determinant capture") (13): during antigen processing,
the unfolding HEL molecule is efficiently captured by the
Ab molecule, preempting other MHC molecules from binding to
this determinant. Strikingly, 11/14 (78.6%) of [B10.A(4R) x
CBA/J]F1 mice raised a proliferative response to peptide
30–53 following immunization with native HEL in comparison to 3/21
(14%) of (B6 x CBA/J)F1 mice. These results suggest
that determinant capture might be the major contributing factor to the
loss of response to p30–53 in (B6 x CBA/J)F1 mice
(Fig. 1). Furthermore, other additional
mechanism(s) might be contributing to the loss of response to this
determinant in a subset of both these F1 strains.
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Contrary to the above-mentioned loss of response to one or more of
HEL determinants in a subset of F1 mice, some groups of
F1 mice challenged with native HEL responded to a new
determinant to which neither parental strain responded. For example, a
subset of (B6 x BALB/c)F1 mice responded to peptide
11–25 of HEL (Table III
). To determine which of the parental strains
was potentially capable of contributing the requisite T cell repertoire
to F1 mice responding to a new determinant of HEL, we
immunized B6 and BALB/c mice with HEL peptide 11–25. After 9 days, the
draining LNC were tested using the same peptide as well as native HEL.
The results given in Fig. 2 show that
BALB/c but not B6 mice responded to HEL peptide 11–25, suggesting that
the BALB/c parent contributes to the responsiveness of (B6 x
BALB/c)F1 mice to HEL p11–25.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is important to realize that an apparently homogeneous response (e.g., a similar pattern of T cell response to the native, whole autoantigen, autoantibody profile and isotype, organ-specific pathology, and clinical disease, etc.) can be observed in some autoimmune F1 situations, such as the (NZB x NZW)F1 model of lupus and peptide-induced EAE in (B10.PL x SJL)F1 mice. Our results suggest that the heterogeneity of response of individual F1 mice of the same strain would not have been evident were the readout based on the proliferative response to either the whole Ag or to only one of its major, dominant determinant(s), or upon induction of a particular disease by a peptide comprising one major, dominant determinant of an Ag. Under these conditions, it would appear, although superficially and incorrectly, that all mice of a particular F1 strain were producing an identical immunologic response. In this regard, using multiple dominant and subdominant determinants of HEL for analysis, our study has provided a novel as well as more accurate, determinant-specific perspective on the heterogeneity of individual F1 mice. Interestingly, the parental (haplotype-specific) bias observed in (B6 x BALB/c)F1 mice in this study has also been observed in studies on a) the T cell response to myelin basic protein in (SJL x B10.PL)F1 mice (22, 23), and b) cytotoxic T cell responses to H-Y Ag in diverse types of F1 mice (24, 25). The novel aspect of our study is the determinant-specific perspective of the heterogeneity of individual F1 mice.
There are at least five major factors that could contribute to the heterogeneity of T cell response to HEL of individual F1 mice as well as to their determinant-specific bias:
1) Alterations in the expression of a particular MHC molecule in F1 mice.
It has been demonstrated that there is a direct relationship between the amount of Ia (MHC) Ag expressed on the APC and the magnitude of the T cell proliferative response to an Ag (26, 27, 28, 29). Generally, a F1 mouse would be expected to express on its APC approximately half of the amount of a particular MHC class II molecule derived from one of its parents. Contrary to this expectation, there is experimental evidence to show that the expression of certain homozygous parental MHC molecules can be significantly altered in F1 mice (28, 29, 30, 31, 32, 33). This decrease was attributable to either a significantly increased expression of hybrid MHC molecules of mixed haplotypes or to complex interactions between different MHC gene products.
2) In hybrid F1 mice, expression of "unique haplotype mixtures" can lead either to a gain or a loss of the T cell response to an antigenic determinant.
It is now well established that in homozygous inbred strains of mice as
well as in hybrid F1 mice, T cell responses to several Ags
can be restricted by hybrid I-A or I-E MHC molecules of intraisotypic
(e.g., A
k, Aßb) or mixed-isotypic (e.g.,
Aßd, Eßd) origin (14, 22, 33, 34, 35, 36, 37, 38, 39).
Moreover, owing to the preferential pairing of certain chains (e.g.,
Eßu with Enon-u), some haplotypes have the
advantage of quantitatively higher expression compared with other
haplotypes in the same animal. Interestingly, it has been suggested
that specific lymphokines or combination of lymphokines could induce
the expression of haplotype-mismatched MHC molecules on certain cell
types (40, 41). This could be one of the reasons why certain autoimmune
diseases are triggered by viral or bacterial infections, which would
provide the required cytokine milieu during inflammation/infection (42, 43). We suggest that alterations in the level of hybrid MHC molecules
on F1 APC can contribute to the variations in T cell
response of these mice in three ways: a) binding to, and presentation
of, new antigenic determinant(s); b) decreasing the expression of one
of the homozygous parental MHC molecules (28, 29, 30, 31, 32, 33); and c) participation
in positive/negative selection of the T cell repertoire, which would
have a direct effect on the expressed phenotype of the F1
mice. Most pertinently, the proportion of chimeric molecules might be
very low (about 1%), and, nevertheless, the determinant so restricted
may be dominant (39), and the level of the chimeric molecule may differ
among individuals.
3) Determinant capture.
During Ag processing, the unfolding HEL molecule is efficiently captured by a particular MHC class II molecule, preempting other MHC molecules from binding to the same determinant(s) or to other nearby determinants on the same molecule. When there are several MHC molecules, a set of competitions is set up among the different MHC competing for the available sites and, depending on the initially most available determinant and its affinity for the ambient MHC, a hierarchy of response will emerge. The increased expression of a hybrid MHC molecule might be an additional factor in this equation. Most importantly, determinant capture not only can result in display of a new dominant determinant, but regularly leads to abrogation of the response to certain other (cryptic) determinants. Of particular importance to the heterogeneity of response among individuals, as more class II molecules join into the competitive milieu and more exo- and endopeptidases become available, greater levels of unpredictability result. As a direct consequence of determinant capture, any individual differences in endopeptidase cleavage(s) will lead to new opportunities for competition among MHC molecules, with an unpredictable outcome.
4) Variations in the level of proteases within hybrid F1 APC.
It is not known how heterogeneous the qualitative and/or quantitative expression of various proteases is within APC from inbred mouse strains of different MHC haplotypes or background genes or from hybrid F1 mice. Furthermore, differential requirements of certain proteases for generation of different determinants from a native Ag (44, 45, 46) or vulnerability of certain determinants to proteolytic destruction (47, 48) could contribute to heterogeneity of the response of F1 mice.
5) Alterations in the T cell repertoire in F1 mice.
Actually, the thymic development of the repertoire is an aleatory process, even with a single class II MHC molecule. With the various points mentioned above, an even greater level of unpredictability can be expected. Furthermore, development of the T cell repertoire (49, 50) of a F1 individual will be significantly influenced by the spectrum of self-determinants displayed in the thymus, which in turn depends on the nature and relative proportion of self-peptides contributed by the two parents and on the quantity and quality (type) of MHC molecules displayed on thymic APC. The latter can lead to a) the loss of a subset of the T cell repertoire as a consequence either of tolerance induction through negative selection (6, 37, 51) or of deletion of a particular TCR Vß specificity through minor lymphocyte stimulating (Mls)Ags (52, 53); b) the failure of positive selection (28, 29, 54); and c) a gain of diversity in the T cell repertoire (7, 12, 33, 37, 38, 54, 55, 56). In addition, environmental agents/Ags can have a significant effect on the T cell repertoire (21, 57).
We have discussed above five important components of the immune system that can contribute to the heterogeneity of response of F1 mice. It is important to realize that each of these components per se is influenced by common elements of competitiveness and the aleatory nature of the event. Because of the unpredictability of each of the five components mentioned above, and the obvious interdependence of most of these elements, e.g., of determinant capture on the position of endopeptidase attack, an even higher level of unpredictability characterizes responsiveness in the F1 animal. Therefore, given the scrambling of the type (haplotype) and level of MHC expressed on APC surface, and the varying constellation of TCR specificities and Ag-processing enzymes in different individuals, it is clearly most difficult to predict the pattern of response to a multideterminant Ag in individual F1 mice.
The results of our study have important implications in understanding the susceptibility or resistance of different members of genetically heterogeneous human populations, or even members of the same family, to a viral/bacterial infection or to a particular autoimmune disease. An efficient and appropriate response to a key determinant of an infectious agent might be protective and life saving. For example, in murine leishmanial infection, a Th1 response to a key parasitic Ag is protective, whereas a Th2 response is pathogenic (58). On the contrary, if susceptibility to an autoimmune disease is determined by a T cell response to a particular determinant within an autoantigen, then only those individuals in whom this determinant is efficiently displayed to the appropriate T cells might contract this disease, whereas others may well be resistant to the same disease (59). For example, mixed (hybrid) MHC molecules in a heterozygous individual could be instrumental in presentation of novel or disease-inducing autoantigenic determinants to T cells (22, 33, 35), e.g., lupus causation in (NZB x NZW)F1 mice (33). On the other hand, determinant/peptide capture (12, 13) or deletion of a particular TCR Vß specificity by an MHC molecule (52) have been implicated in protection from diabetes. Furthermore, our results described above and those of others (32, 60, 61) suggest that a particular susceptibility gene or locus, in combination with another allele, might significantly change the susceptibility pattern of the individual, either enhancing susceptibility or affording protection from disease. For example, heterozygous individuals with HLA-DR3/DR4 are highly susceptible to diabetes, whereas those with HLA-DR2/DR3 or HLA-DR2/DR4 are less likely to develop diabetes (60). However, our results point to the inherent uncertainty that a particular combination of haplotypes will actually be protective in every instance.
Our findings also have direct application to vaccination with protein Ags. These results suggest that even in a human population sharing a MHC allele capable of response to a key antigenic determinant of a vaccine, a great diversity would be evident among individuals, and some would not be protected; inexplicably, certain individuals would not respond to this determinant within the protein. What is clear is that the response of one or both parents is only minimally predictive of the response of the offspring. In the case of the heterozygous human population, where segregation occurs to complicate the genetic picture, prediction of a vaccine’s protective response is hazardous, despite the known presence of the restricting MHC molecule(s).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Eli E. Sercarz or Dr. Kamal D. Moudgil, Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121. E-mail address:
3 Abbreviation used in this paper: HEL, hen eggwhite lysozyme; LNC, lymph node cells, SI, stimulation index.
Received for publication January 10, 1997. Accepted for publication August 7, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and E chains results in a quantitative deficiency in expression of an A:E complex. J. Exp. Med. 155:490.:E complex expression causes a corresponding defect in antigen-presenting cell function. J. Exp. Med. 155:508.bAßk hybrid Ia molecules restrict the response towards the glutamic acid A4 epitope. Scand. J. Immunol. 20:97.[Medline]
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