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The Journal of Immunology, 1998, 161: 148-153.
Copyright © 1998 by The American Association of Immunologists

Strong Alloantigenicity of the {alpha}-Helices Residues of the MHC Class I Molecule1

Ghada Noun*, Murielle Reboul*, Jean-Pierre Abastado{dagger}, Philippe Kourilsky{dagger}, François Sigaux* and Marika Pla2,*

* Mouse Immunogenetics, U462, Institut National de la Santé et de la Recherche Médicale, Institute of Hematology, Paris, France; and {dagger} U277, Institut National de la Santé et de la Recherche Médicale, Pasteur Institute, Paris, France


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
To evaluate the role of single residues of a MHC class I molecule in the induction of a primary allogeneic response, we have tested the ability of various point mutants (of the {alpha}-helices or ß-sheet of the {alpha}1 and {alpha}2 domains) of the Kd molecule to induce a primary cytotoxic T cell response in mice carrying the wild-type molecule. For that, we have used an in vivo model in which cells expressing mutant molecules were injected into the hind footpads of mice carrying wild-type Kd, and the recipient graft-draining popliteal lymph nodes were tested for the presence of alloreactive CTL. Under these experimental conditions, only 7 of the 25 mutant Kd molecules induced a primary allogeneic response. All of these mutations (positions 62, 65, 69, 72, 155, 163, 166) concern residues of the {alpha}-helices, demonstrating that very small variances from self in a class I molecule, located outside the peptide-binding groove, can be antigenic. To determine the peptide requirements for the generation of a primary allogeneic response, we have analyzed the repertoire of peptides selected by individual mutant molecules shown to be able or unable to induce a CTL response. No correlation was observed between the peptidic make-up presented by a given mutant and its capacity to induce a primary allogeneic response. On the whole, our data point to the alloantigenicity of potentially TCR-contacting surface residues of the MHC class I molecules.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The main target molecules during allograft rejection are the MHC molecules. Allogeneic responses can be elicited by both the MHC class I and class II proteins. Thus, Ag-presenting molecules themselves become Ags. That special case, in which T cells recognize allogeneic or xenogeneic MHC molecules as intact structures on the surface of foreign cells, is called direct T cell recognition.

Much research has been undertaken to unravel the molecular basis of allorecognition and, in particular, to determine the nature of the antigenic determinants involved in the direct alloreactive T cell recognition (1, 2). The data clearly demonstrate the existence of peptide-specific alloreactive T cells (3, 4, 5, 6, 7). Several studies have suggested the presence of peptide-dependent, but not peptide-specific, CTL (8, 9, 10). CTL clones that seem to recognize the allogeneic MHC molecule in a peptide-independent fashion have also been reported (11, 12).

While much research has been focused on the structure recognized by effector cells, relatively little has been performed on determining the peptide requirements for the generation of alloreactive T cells. As a part of our continuing effort to study the alloantigenic structures of class I molecules, we have compared the capacity of various point mutants (with amino acid changes located on the {alpha}-helices or on the ß-sheet of {alpha}1 and {alpha}2 domains) of an H-2 class I molecule to induce a primary allogeneic response. We have used an in vivo model in which the cells expressing allogeneic MHC molecules were injected into the hind footpads of the recipient mouse, and the graft-draining popliteal lymph nodes were tested for the presence of alloreactive CTL. We report in this work an application of this model allowing the induction of CTL in draining lymph nodes of mice carrying wild-type Kd molecules by local graft of cells expressing various mutant Kd molecules, thus ensuring that the incompatibility between donor and recipient is limited to only one amino acid located either on {alpha}-helices or on ß-sheet. In parallel, using a library of 648 synthetic peptides, we have measured the binding capacity of individual mutant molecules. Our results show that there is no correlation between the peptidic make-up presented by a given mutant and its capacity to elicit a primary allogeneic T cytotoxic response and underline the role of residues located on the {alpha}-helices in the induction of primary allogeneic T cell responses.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Animals

All mice were bred and maintained in our own colony (Mouse Immunogenetics, U462, Institut National de la Santé et de la Recherche Médicale, Institute of Hematology, Paris, France). The F1 mice used in this work were obtained from the crosses of B10.BR (Kk Dk) with C3H.OL (Kd Dk) mice.

Cells

Transfected cells are mouse L fibroblasts (H-2k) expressing wild-type (Kd) or mutated (Kdm) H-2Kd molecules in addition to MALA-2 adhesion molecule. All mutations are single alanine substitutions performed by site-directed mutagenesis on full-length wild-type H-2Kd cDNA, and are located either on the ß-sheet or on the {alpha}-helices. Alanine has been chosen for replacements because it has the smallest lateral chain with chirality and has been used successfully in other studies (13, 14). LM1 cells are L fibroblasts transfected only with MALA-2 gene (15, 16). Con A-induced blasts (Con A blasts) used as target cells in cell-mediated lympholysis (CML)3 assays were prepared by incubating 4 ml of spleen cell suspension (5 x 106/ml) with Con A (Sigma, St. Louis, MO; 5 µg/ml) for 48 h in culture medium.

Monoclonal Abs

For the CML-blocking experiments, the following mAbs were used as hybridoma culture supernatants: 16.3.22S, Kk reactive (17), and 34.1.2S, Kd reactive (18). For the immunoprecipitation assays and flow-cytometry analysis, the Kd-reactive SF1-1.1.1 mAb (ATCC HB159) was used.

In vivo generation of alloreactive CTL

Recipient mice were injected with 107 irradiated (55 Gy) fibroblasts into the hind footpads. After 3 days, cell suspensions were prepared from the draining lymph nodes and the cells were cultured for 4 more days in vitro in the absence of any stimulating cells, in culture medium containing Con A-stimulated rat spleen cell supernatant as a lymphokine source (50 U IL-2/ml). The culture medium was MEM {alpha}-medium (Life Technologies, Gaithersburg, MD) supplemented with 100 U/ml penicillin (Life Technologies), 100 µg/ml streptomycin (Life Technologies), 2 mM glutamine (Life Technologies), 5 x 10-5 M 2-ME (Sigma), and 10% heatinactivated FCS.

CML assay

Five thousand 51Cr-labeled target cells were incubated with primary in vivo induced CTL at various E:T ratios in round-bottom wells for 4 h. The percentage of specific 51Cr release was calculated as: (experimental - spontaneous release)/(maximum - spontaneous release) x 100. Specific lysis was calculated as the difference between the percentages of specific 51Cr release from Kdm-expressing and Kd-negative (LM1) target cells at a 100:1 E:T ratio. For Ab inhibition experiments, the target cells were incubated with Abs for 30 min before addition of the effector cells. The percentage of inhibition was calculated as: (1 - (specific lysis with mAb/specific lysis without mAb)) x 100.

Flow cytometry

Cells (5 x 105) were incubated successively with saturating concentrations of SF1-1.1.1 mAb and FITC-conugated goat F(ab')2 anti-mouse Ig (Jackson ImmunoResearch, West Grove, PA). Both incubations were conducted on ice for 30 min, and were followed by two washing steps. Stained cells were analyzed using a FACScan flow cytometer (Becton Dickinson, Mountain View, CA).

Soluble Kd molecules

The single-chain Kd molecules (SC-Kd) were obtained by covalently connecting the Kd heavy chain to murine ß2-microglobulin by a 15-amino-acid-long spacer (19). Single alanine substitutions of the wild-type SC-Kd were produced by site-directed mutagenesis, as previously described (20).

Peptides

The peptide library used in the immunoprecipitation assay has been previously described (20, 21, 22). Briefly, it was obtained by coupling multiple amino acid residues at each successive cycle of peptide synthesis. Amino acid residues were as follows:

RYNPVYTEL VFLAN KK T S EY

Peptides were labeled by chloramine T-catalyzed iodination.

Immunoprecipitation and peptide analysis

Purified SC-Kd (1–10 µg) was incubated in PBS with 2 to 6 µM iodinated peptides for 3 h at room temperature or overnight at 4°C. SC-Kd-peptide complexes were immunoprecipitated using an excess of the SF1-1.1.1 mAb and protein A beads (Pharmacia LKB Biotechnology, Uppsala, Sweden). After three washes, bound peptides were eluted from the immunoprecipitates by three acid extractions in 200 µl of 1% trifluoroacetic acid for 10 min, centrifuged through 0.22-µm cellulose acetate filters (Costar, Cambridge, MA), lyophilized, and separated by reverse-phase HPLC on a C8 RP300 HPLC column (Brownlee Labs, Marrieta, CA) using a linear (5–35%) acetonitrile gradient. Radioactivity in the individual fractions was counted. Fractions were then lyophilized and applied to plates made of silica gel 60 (Merck, Darmstadt, Germany). TLC was performed in an N-butanol:H2O:pyridine:acetic acid ratio of 2:1:0.75:0.25 (20, 21, 22).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Direct recognition of the Kd molecule by primary CTL induced in draining lymph nodes by injections of class I-transfected fibroblasts

To characterize primary in vivo induced anti-class I CTL, and especially those involved in graft rejection, we have utilized an in vivo model based on our previous observation (23) that injection of spleen cells from allogeneic mice into the hind footpads leads to the development of CTL within the draining lymph nodes. This procedure allows the induction of CTL activated in vivo in response to a local graft of cells expressing allogeneic class I molecules. In the present experiments, fibroblasts expressing wild-type or mutated Kd molecules were injected into the hind footpads of the recipient mouse. The draining popliteal lymph node cells were cultured for 4 more days in the absence of any stimulator cells. After this period, required to allow full differentiation of the sensitized CTL precursors (24), the lymph node cells were tested for the presence of CTL using a 51Cr-cytotoxic assay. It was necessary to ascertain that the transfected class I molecules carried by the fibroblasts, which are nonlymphoid cells, are able to induce CTL that recognize MHC class I molecules as intact structures on the cell surface, through direct recognition. For that, B10.BR (H-2k) mice were immunized, as described above, with fibroblasts carrying wild-type (L-Kd) or mutated (Q114A) Kd molecules, and the CTL were tested on the fibroblasts used for the induction (Kd or KQ114A, Kk, Dk) as well as on Con A blasts from B10.D2 (Kd, Dd) and (B10.BR x C3H.OL)F1 (Kd, Kk, Dk) mice. As shown in Figure 1Go, a comparable lysis of B10.D2, (B10.BR x C3H.OL)F1, L-Kd, and Q114A targets was observed, suggesting that the elicited primary cytotoxic response is composed mainly of CTL that recognize Kd as an intact molecule (direct recognition), and not as a Kd-derived peptide presented by a MHC molecule of the H-2k haplotype.



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  		FIGURE 1. Primary in vivo induction of Kd-reactive CTL in mice of the H-2k haplotype immunized with fibroblasts expressing wild-type or mutated Kd molecules. H-2k mice were injected into the hind footpads with irradiated fibroblasts expressing wild-type (L-Kd) or mutated (Q114A) Kd molecules, and draining lymph node cells were tested for anti-Kd cytotoxic activity in a 4-h 51Cr release assay. The targets used are stimulator fibroblasts and Con A blasts from B10.BR (Kk, Dk), B10.D2 (Kd, Dd), and (B10.BR x C3H.OL)F1 (Kd, Kk, Dk) mice.

 
In vivo induction of a primary anti-Kdm cytotoxic response in Kd-expressing recipients

Twenty-five mutants of the Kd molecule, in which different residues located on the {alpha}-helices (12 mutants) and on the floor (13 mutants) of the Ag binding site were substituted by alanine (Fig. 4Go), were used to evaluate the role of single amino acids in the induction of a primary allogeneic response. The single-point mutant Kd molecules (Kdm) were tested for their ability to elicit an anti-Kdm cytotoxic response in mice expressing the wild-type Kd molecule. (B10.BR x C3H.OL)F1 mice were injected with fibroblasts carrying the various Kdm molecules, and draining lymph nodes CTLs were tested for an anti-Kdm cytotoxic activity. Three to six independent experiments were performed for each of the Kd variants. As shown in Figure 2Go, most of the mutated Kd molecules failed to induce a primary CTL response. Only 7 of the 25 Kdm tested, carrying mutations at positions 62, 65, 69, 72, 155, 163, or 166, were consistently able to elicit significant cytotoxic responses in Kd-positive mice. The CTL elicited by one of these mutants (E163A) were further analyzed using Ab-blocking experiments. As shown in Figure 3Go, a very efficient inhibition of the lysis of E163A targets was achieved by preincubation of target cells with a Kd-reactive mAb (34.1.2S), which also binds E163A. On the contrary, preincubation of the target cells with a Kk-reactive mAb (16.3.22S) had no inhibitory effect on the lysis. These results further support the observation that the majority (if not all) of the alloreactive CTL raised in our experimental protocol against the Kdm molecule directly recognize the allogeneic molecule at the cell surface.



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  		FIGURE 4. Location of the alanine-substituted residues on the Kd molecule according to the equivalent residues determined for HLA-A2 (25–27). Mutations that were able to induce a primary allogeneic response in mice expressing the native Kd molecule are indicated by bold ovals.

 


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  		FIGURE 2. Primary CTL induction in (B10.BR x C3H.OL)F1 mice injected with fibroblasts expressing mutated Kd molecules. The presence of CTL reactive with mutant molecules was detected using a standard 51Cr release assay. Specific lysis (%) is calculated as described in Materials and Methods for an E:T ratio of 100:1. Values are means of three independent experiments. As the lysis of Kd-negative target cells never exceeded 10%, a CML result was scored as positive (black bars) when >15% specific lysis occurred. For the mutants nomenclature, the number indicates the position of the mutated residue, and the first and last letters are the single-letter codes for wild-type and alanine-substituted residues, respectively.

 


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  		FIGURE 3. Inhibition of the reactivity of primary E163A-reactive CTL on fibroblasts expressing the E163A variant by mAb reactive with Kk (16.3.22S, white bar) or Kd (34.1.2S, which recognizes E163A, black bars). The percentage of inhibition was calculated as described in Materials and Methods. The E:T ratio was 100:1.

 
All of the mutations that were capable of inducing an allogeneic response concern surface residues located on the {alpha}-helices (Figs. 2Go and 4Go) with side chains pointing up toward the TCR (25, 26, 27, 28). A crystallographic study (29) has shown that recognition by a TCR of peptide complexed with a MHC molecule occurs through variable loops in the TCR structure that bury almost all of the available peptide and a much larger area of the MHC molecule. Interestingly, residues 65, 69, 72, 155, and 163 of the MHC molecule shown (29) to interact with the TCR through van der Waals contacts induced, when mutated, a primary allogeneic response in graft-draining lymph nodes. Concerning ß-sheet mutants, whose mutated residues contribute to the conformation of the peptide-binding groove, none of them was able to provoke an allogeneic response.

Analysis of the repertoire of peptides selected by Kd variants

To determine the role of the peptides bound by the Kd variants with respect to their ability to induce an allogeneic response, we have analyzed the peptide-binding capacity of five of the Kd mutants (Q65A, S69A, E163A, R97A, and Q114A), in comparison with that of the wild-type Kd molecule. Each of these Kd variants, produced as secreted single chains, was loaded with 648 synthetic 125I-labeled peptides containing the Kd-binding motif. The MHC-peptide complexes were then purified by immunoprecipitation, and the eluted peptides were separated by reverse-phase HPLC. As shown in Figure 5Go, the HPLC profiles obtained with the Q65A and S69A {alpha}-helices mutants were very similar to that obtained with the wild-type Kd molecule. In contrast, the profiles of peptides picked up by the R97A and Q114A ß-sheet mutants were different. Moreover, the two-dimensional profiles obtained with R97A and Q114A molecules in our previous study (20) revealed that these two mutants bind the same peptides as wild-type Kd, plus a large set of additional peptides.



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  		FIGURE 5. HPLC analysis of peptides selected by Q65A, S69A, R97A, and Q114A Kd variants (dark lines). The profile of peptides bound to the wild-type Kd is superimposed for comparison (gray lines). Soluble Kd or Kdm molecules were incubated with the 125I-labeled peptide library, then precipitated with SF1-1.1.1 mAb. Bound peptides were acid eluted from the immunoprecipitates and separated by reverse-phase HPLC, and the radioactivity in the individual fractions was counted.

 
To detect eventual differences between the sets of peptides bound by the {alpha}-helices mutants and the wild-type Kd molecule, which could not be revealed by HPLC analysis, the HPLC-separated peptide fractions were further resolved by TLC. The two-dimensional analysis of the peptides bound by the {alpha}-helices variants or by the wild-type Kd was remarkably similar (Fig. 6Go). Despite the fact that the two-dimensional profiles obtained with S69A, E163A, and the wild-type Kd showed no differences, both mutants were able to induce (Fig. 6Go) a strong primary cytotoxic response in recipients expressing wild-type Kd molecules.



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  		FIGURE 6. Two-dimensional analysis of the peptides selected by wild-type Kd, S69A, and E163A. HPLC-separated peptide fractions (x-axis) were lyophilized and further resolved by TLC (y-axis). The lytic activity of effectors raised in (B10.BR x C3H.OL)F1 mice against S69A and E163A is also shown.

 
Based on this peptide-binding analysis, it appears that mutation of {alpha}-helices residues 65, 69, or 163 does not influence the range of bound peptides, consistent with the modeling studies that predict that these residues do not contribute to the conformation of the peptide binding site (26, 27, 30). These data suggest that the response raised against these {alpha}-helices mutants is not based on a modification of the set of peptides bound by these mutants and that the mutated residues might be directly involved in the TCR recognition. Another explanation might be that these CTL have broken tolerance to self peptides by seeing them in a new context of mutated Kd molecules. In a study made by Grandea et al. (31, 32), Kb molecules mutated at residues 65 and 69 were able to provoke strong alloreactive T cell response in mice expressing the native Kb molecules. The mutant-specific alloreactive CTL were specific for self peptides extracted from wild-type Kb molecules and recognized in the context of the mutant Kb molecules. Thus, the T cell repertoire is reactive to very subtle changes away from self.

Of 25 Kd variants, bearing single amino acid substitutions spread on the {alpha}-helices (12) and on the ß-sheet (13), only seven Kdm, all of them located on {alpha}-helices, were able to induce a primary allogeneic response. None of the 13 Kd mutants located on the ß-sheet was able to elicit a significant primary cytotoxic response in Kd-expressing recipients. The difference between the {alpha}-helices and the ß-sheet variants in their capability to induce a primary allogeneic response could not be attributed to any particular defect of the ß-sheet mutants. First, this difference could not be correlated with the variation in expression levels observed among the Kd transfectants, as detected by cytofluorometric analysis using SF1-1.1.1 mAb (Fig. 7Go). This mAb defines an antigenic determinant located on the {alpha}3 domain, untouched by site-directed mutagenesis (20, 33), and can thus be assumed to recognize equally well all mutant Kd molecules. The minor differences in the expression levels of the various mutant molecules (Fig. 7Go) cannot account for the lack of immunogenicity of the ß-sheet mutants. For example, ß-sheet mutants R97A and Q114A expressed at levels comparable with those of {alpha}-helices mutants (E62A, Q72A, Y155A, and E166A), which readily provoked an allogeneic response (Fig. 2Go), failed to induce an allogeneic response in Kd-expressing mice. Furthermore, the ß-sheet mutants were recognized by anti-Kd-alloreactive (unpublished data) and Kd-restricted (15) CTL clones, providing support for their conformational integrity. Finally, when injected in B10.BR (H-2k) mice, the ß-sheet mutants were able to induce primary CTL that recognize equally well target cells expressing wild-type and mutated Kd molecules (data shown for mutant Q114A, Fig. 1Go).



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  		FIGURE 7. Flow-cytometry analysis of the cell surface expression of native and mutant Kd molecules. FACS analysis was performed using the Kd-reactive SF1-1.1.1 mAb. Dashed histograms correspond to the fluorescence of cells incubated only with FITC-conjugated goat F(ab')2 anti-mouse Ig. Values in italic are means of fluorescence (arbitrary units).

 
In a study made by Pullen et al. (34) using mice expressing wild-type or mutated Kd molecules, it was shown that the substitution of residue 114 (Q to E) in the Kd molecule (Kdm4) leads to changes in the spectrum of bound peptides, as demonstrated by the analysis of the pool of naturally processed peptides, and is able to elicit an alloreactive response in an in vitro H-2d anti-Kdm4 MLC. The incapability of our Q114A mutant to induce a primary allogeneic response might be due to some differences between the two models. The mutant molecules Kdm4 and Q114A have different substituted amino acid at position 114 (E and A, respectively). Moreover, the recipient mice used in the two models differ in their H-2 haplotypes and could therefore have shaped different T cell repertoires. Finally, the stimulator cells used in our study are fibroblasts that do not express costimulator molecules such as B7 that facilitate TCR triggering and lower the activation threshold.

Nevertheless, in our experimental conditions, a significant number of {alpha}-helices mutants (7 of 12) were able to induce a primary allogeneic response, whereas none of the 13 ß-sheet variants did. The {alpha}-helices Kd variants thus appear to be very immunogeneic, probably because all of the self peptide-filled mutant molecules are potentially different from the wild-type molecules bearing the same self peptides. As for the ß-sheet variants, even if they do bind a new range of peptides as compared with Kd, a given peptide type would occupy only a fraction of the available Kdm molecules, and would thus be represented at a rather low density corresponding to that of conventional antigenic peptides. Thus, it might be that the density of a determinant rather than its nature is important for the induction of a primary allogeneic response. Striking examples are mutant S69A, for which a modification limited to one hydroxyl group is sufficient to generate an allogeneic response, and mutants R97A and Q114A that, although they do bind a large set of additional peptides as compared with the wild-type molecule (Fig. 5Go) (20), fail to induce an allogeneic response.

In conclusion, we have provided additional insight into the nature of the alloantigenic determinants carried by MHC class I molecules, demonstrating that amino acid substitutions in the ß-sheet that could affect peptide-binding specificity have lesser effects on the generation of primary CTL than substitutions at positions on {alpha}-helices that point toward the TCR with no discernible effects on peptide binding. This observation may be of importance in the evaluation of the outcome of allogeneic grafts.


   Acknowledgments
 
We thank B. Frangoulis for critical reading of the manuscript, M. Chopin for her valuable help with in vivo experiments, A. Casrouge for the preparation of wild-type and mutant SC-Kd molecules, and H. Ploegh for the gift of the peptide library.


   Footnotes
 
1 This work was supported by institutional grants from the Institut National de la Santé et de la Recherche Médicale. G.N. is a recipient of a fellowship provided by Association Claude Bernard. Back

2 Address correspondence and reprint requests to Dr. Marika Pla, Mouse Immunogenetics, U462, Institut National de la Santé et de la Recherche Médicale, Institute of Hematology, 1, avenue Claude Vellefaux, 75010 Paris, France. E-mail address: Back

3 Abbreviation used in this paper: CML, cell-mediated lympholysis. Back

Received for publication October 31, 1997. Accepted for publication March 2, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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