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. 2003 Apr;132(1):46–52. doi: 10.1046/j.1365-2249.2003.02115.x

Differences in MHC-class I presented minor histocompatibility antigens extracted from normal and graft-versus-host disease (GVHD) mice

BRULEY M ROSSET *,‡, V TIENG †, D CHARRON †, A TOUBERT †
PMCID: PMC1808673  PMID: 12653835

Abstract

Graft-versus-host disease (GVHD) may develop after allogeneic bone marrow transplantation (BMT) between donors and recipients incompatible for minor histocompatibility antigens (mHAg). Here, we examined the possible relationship between tissue-specific distribution of dominant mHAg peptides and specific organ destruction caused by GVHD. In the B6 anti-Balb/b (H-2b) strain combination, a GVHD developed against Balb/b mHAgs. Despite the high number of incompatible mHAgs between these two strains, both cytotoxic T lymphocyte (CTL) response and GVHD could be attributed to a limited number of dominant mHAgs. We studied CTL-defined expression of dominant mHAgs in normal tissues and their GVHD-related modifications. mHAg peptides were prepared by acid elution and reversed-phase high pressure liquid chromatography fractionation from the spleen, liver, gut and skin as GVHD target tissues and from the heart and kidney as control tissues. Peptidic fractions extracted from normal and GVHD tissues were incubated with RMA-S targets and analysed using bulk B6 anti-Balb/b CTL. In each tissue several fractions were recognized with a given pattern of mHAg expression. GVHD induced qualitative and quantitative changes in antigenic peptide expression. Modifications in mHAg presentation during GVHD concerned preferentially GVHD target organs as opposed to non-GVHD target organs. In addition, when immunizing tissues were derived from GVHD mice instead of normal mice, the profile of CTL recognition was different. In conclusion, these data indicate that broad differences could exist in peptide presentation between various normal and GVHD-target organs.

Keywords: allogeneic bone marrow transplantation, cytotoxic T lymphocytes, graft-versus-host disease, minor histocompatibility antigens, peptide elution

Introduction

In allogeneic bone marrow transplantation (BMT), disparity between donors and recipients at the level of minor histocompatibility antigens (mHAg) may cause an adverse graft-versus-host disease (GVHD) [1,2]. mHAgs are naturally processed peptides derived from normal intracellular proteins with several allelic forms and presented to T cells in association with major histocompatibility complex (MHC) class I or class II molecules [3]. These antigens have been described to display tissue-restricted expression [4–7] and low polymorphism [4,8]. Identification of their amino acid sequence progressed recently both in the case of human [7,9–12] and mouse mHAgs [13–17]. Many different mHAgs, identified by their ability to induce cytotoxic T lymphocyte (CTL) or to cause skin graft rejection or GVHD after allogeneic BMT, exist in mice as well as in humans. Despite the high number of incompatible mHAgs between two individuals, CTL responses could be attributed to a very limited number of dominant antigens [5, 7, 8, 18]. Similarly, using different recombinant inbred mouse strains, dominant mHAgs were also observed during GVHD which develops after BMT within the same genetic combination [19]. Additionally, although all dominant mHAgs induce CTL, it is obvious that they are not all equally important in the development of GVHD: first, not all mismatched grafted patients suffer from GVHD [1] and secondly, only around 50% of bone marrow grafts between H-2 matched donor/recipient mice combinations develop a lethal GVHD [20]. mHAgs are tissue-restricted [4–7] and GVHD preferentially affects specific organs such as the liver, gut, skin and lymphoid tissues [21]. Thus, mHAgs may be expressed differently on GVHD target organs and on spleen cells responsible for CTL generation. Indeed, using the peptide acid elution technique followed by biochemical separation and detection by specific T cell lines or clones, Griem et al. [22] demonstrated that naturally processed peptides specific for H-4, H-Y and mapki antigen show an individual tissue distribution and that the relative amount of individual peptides may be highly variable. The gut, spleen, liver, thymus, lung and kidney express high levels of these antigens, whereas they were not detected in the brain, muscle and heart.

In addition to the tissue-specific distribution of mHAgs on normal organs, mHAg expression, and therefore immunogenicity, might be modified in mice developing GVHD after allogeneic BMT because (1) lethal irradiation leads to the rapid destruction of bone marrow-derived host cells which are replaced by cells of donor origin, thereby changing the APC (antigen-presenting cell) composition of the BMT recipient and (2) as MHC class I molecules govern the expression of mHAg peptides [22], the local release of cytokines during GVHD [23] may increase or even induce the expression of MHC molecules in tissues that were negative in normal individuals, thereby modifying mHAg presentation.

To explore the total expression of dominant mHAgs recognized by bulk CTL in different tissues of normal mice or of mice that develop a GVHD across the same mHAgs, we used the C57Bl/6 (B6) anti-Balb/b (B/b) strain combination that differs in more than 40 mHAgs [24] but for which a limited number of dominant B/b mHAgs have been defined previously both in CTl [25,26] and in GVHD [19]. In this graft model, B6 donors and B/b recipients were sex-matched to avoid response against male H-Y antigen and GVHD mortality occurred in 80% of recipients with a median survival of 30–40 days [19]. Peptide fractions were prepared from several tissues, some involved in GVHD (spleen, liver, gut and skin) and others not involved (heart and kidney), collected from normal B/b mice and from GVHD mice grafted 14–21 days earlier. We characterized the peptide fractions separated by reverse-phase high pressure liquid chromatography (RP-HPLC) with CTL generated against spleen cells and against each solid tissue derived from both normal and GVHD mice.

Our results demonstrated that (1) although many positive fractions are shared between the different tissues, each tissue has its own individual reactivity profile, (2) it is possible to generate CTL specific for solid tissues and (3) interestingly, qualitative as well as quantitative modifications of mHAg peptide presentation are observed preferentially in GVHD target tissues as opposed to non-GVHD target tissues.

Materials And Methods

Mice

B/b (H-2b) and C57Bl/6 (B6; H-2b) female mice were purchased from Harlan (France) and maintained in our animal facilities.

GVHD induction and follow-up

B/b mice were lethally irradiated (9 Gy) using a caesium source and subsequently transplanted intravenously with 107 bone marrow cells and 2 × 107 spleen cells derived from B6 mice. Lethally irradiated mice died within 14 days. Weight loss served as an indicator of GVHD and mortality occurred in 80% of mice between 30 and 40 days post-transplant [19].

Tissue peptide extraction and HPLC separation

The spleen, gut, liver, skin (GVHD target tissues) and the heart and kidney (control tissues) were collected, weighed and pooled from three to 10 normal B/b mice or lethally irradiated B/b mice that developed GVHD after grafting with B6 cells 14–21 days earlier. The liver and spleen were perfused and washed with phosphate buffered saline (PBS). The other organs were also washed with PBS. Equal amounts of organs were homogenized with an ultraturrax (1 g in 10 ml of 1% TFA (trifluoroacetic acid) (volume/volume in water) and sonicated further for 1 min [14]. After stirring for 1 h on ice, the suspension was then centrifuged for 30 min at 180 000 g and 4°C. Supernatants were collected, filtered on a 30 Kd membrane followed by a 5 Kd Amicon membrane and lyophilized. These preparations were resuspended in 0·1% TFA before HPLC. RP-HPLC was performed on a C18 column (ODS C18, 4·6 × 150 mm, Beckman instruments, Gagny, France) using the Beckman system Gold instrumentation (solvent module 126, UV detector 166). The gradient consisted of 0·05% TFA in H2O/0·05% TFA in acetonitrile 91 : 9 for 10 min followed by a linear increase to 35% acetonitrile-0·05% TFA over 60 min. Absorbance was monitored at 220 nm. Flow rate was 500 µl/min. Fractions of 500 µl were collected with a Gilson 203B collector. RP-HPLC fractioning experiments were calibrated with synthetic peptides to allow comparisons between experiments.

Immunization against tissues and CTL generation

In a first series of experiments, CTL were generated by immunizing B6 mice intravenously with a B/b spleen cell suspension (5 × 106 cells). To obtain CTL against solid tissues, the spleen, gut, liver, skin, kidney and heart from normal or GVHD B/b mice were homogenized with an ultraturrax and emulsified in incomplete Freund's adjuvant (IFA) before injecting subcutaneously in B6 mice twice at a 1-week interval. Spleen cells (2 × 107) were collected from immunized mice and cultured for 5 days in the presence of 2 × 107 irradiated B/b spleen cells.

CTL assays

Various concentrations of stimulated cells were incubated at 37°C for 4 h in the presence of 51Cr-labelled B/b 105 Con A blasts and their capacity to lyse the targets was evaluated. Twenty µl of different peptide fractions (experimental samples) or of medium (control sample) were incubated for 90 min at 27°C on 51Cr-labelled RMA-S targets (H-2b, TAP-deficient cells) and mixed for 4 h at 37°C with effector cells at a ratio of 50 : 1. RMA-S targets cells were preincubated overnight at 27°C before chromium labelling to increase the number of empty MHC molecules at the cell surface. The radioactivity of the supernatant was determined using a γ counter. Specific lysis was calculated with the following formula:

(experimental release−control release)/(maximum release−spontaneous release)×100.

Spontaneous release was given by 51Cr-labelled RMA-S in the presence of medium only and maximum release in the presence of detergent without CTL. A fraction was considered arbitrarily as positive when the lysis of peptide-loaded RMA-S cells by specific CTL exceeded 10%.

Results

Peptides extracted from normal B/b tissues and recognized by CTL generated against spleen cells

CTL generated by immunizing B6 mice with a suspension of normal B/b spleen cells were shown to be strongly cytotoxic to B/b Con A blasts (80% at 50 : 1 E/T) but not to other allogeneic (H-2 incompatible) targets nor to syngeneic B6 (H-2 identical) blasts, thus supporting the hypothesis that T cells are specific to mHAgs expressed on B/b spleen cells (data not shown). Acid eluates extracted from the same weight of normal B/b spleens, livers, gut, skin, hearts and kidneys were separated by HPLC. The individual HPLC profiles revealed a variation between the tissues in the main peak position and in the relative amount of peptides: similar amounts of peptides were extracted from skin, liver, kidney and heart whereas the extraction from gut and especially spleen yielded more peptides (Fig. 1). Therefore, we tested the lytic capability of the CTL raised against B/b spleen cells for 51Cr-labelled RMA-S cells loaded with 20 µl of each of the fractions. The cumulative results (Fig. 2) indicated that for the peptides extracted from the spleen of normal B/b mice, effector cells specific for mHAgs recognized five dominant fractions with individual intensity: 26, 28–29, 56, 62–63 and 72. For peptides extracted from the other tissues, CTL recognized fractions already identified in the spleen but their reactivity pattern was unique for each tissue (Fig. 2). Fractions 28–29 and 62–63 were expressed ubiquitously, although at different levels. However, others were present or not, depending on the tissue examined: for instance, fraction 56–58 was absent from the kidney and skin, and was only weakly expressed in the heart and liver (<15%). Similarly, fraction 26, strongly recognized in all tissues, was totally absent from the heart. Fractions 72–73 was absent from the liver, skin and heart and weakly expressed in the other tissues (<20%). In this series of experiments, no direct correlation could be found between the capacity of a fraction to induce RMA-S lysis by CTL and the size of peptide fractionation peaks in HPLC suggesting strongly that mHAg could be detected functionally even when peptide concentration is very low.

Fig. 1.

Fig. 1

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HPLC profiles of peptide preparations obtained by acid elution of different tissues derived from normal B/b mice. Lyophilisated eluates were resuspended in 0·1% TFA and separated on a C18 column using water/acetonitrile elution gradient; 0·5 ml fractions were collected and tested for recognition with specific CTL.

Fig. 2.

Fig. 2

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Different peptide fractions extracted from normal tissues were recognized by CTL generated against normal B/b spleen cells. B6 responders were primed intravenously with B/b spleen cells and restimulated in vitro with irradiated B/b spleen cells. The CTL obtained were incubated 4 h at an E : T = 50 : 1 with 51Cr-labelled RMA-S cells loaded with 20 µl HPLC fractions prepared from eluates of different tissues collected from normal B/b mice. Results are given as the percentage of specific lysis of peptide-loaded RMA-S cells.

Peptides extracted from GVHD tissues and recognized by CTL generated against spleen cells

The same analysis was performed on peptides extracted from organs of lethally irradiated B/b mice grafted with B6 cells that developed a GVHD. As for normal tissues, the amounts of peptides recovered from GVHD tissues were comparable in skin, liver, kidney and heart as measured by O.D. level but more abundant in spleen and gut (Fig. 3), but HPLC profiles revealed modifications in peak positions. Figure 4 presents the pattern of dominant peptides recognized by anti-B/b normal spleen CTL as used for the detection of peptides extracted from normal tissues. A unique pattern of reactivity for each GVHD tissue was observed as in normal preparations (Fig. 1). Although fractions 28–29 and 61–62 were positive in all GVHD preparations, considerable modifications occurred in the peptide expression after transplantation: (1) fraction 26 was no longer detectable in all GVHD tissues; (2) conversely, fraction 56–57 became detectable in the skin and fraction 71–72 in the heart and liver; and (3) finally, four consecutive fractions (71–74) were positive in the GVHD kidney as opposed to only one (fraction 72) slightly positive in the normal kidney. Therefore, in this first part of the study, we demonstrated that the set of dominant peptides recognized by specific anti-B/b bulk CTL differs not only from one organ to another but also for a given organ when extracted from normal mice or from irradiated recipients developing GVHD following BMT.

Fig. 3.

Fig. 3

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HPLC profiles of peptide preparations obtained by acid elution of different tissues derived from B/b mice grafted 14–21 days previously with spleen and bone marrow cells from B6 mice (GVHD mice). Lyophilisated eluates were resuspended in 0·1% TFA and separated on a C18 column using water/acetonitrile elution gradient. 0·5 ml fractions were collected and tested for recognition with specific CTL.

Fig. 4.

Fig. 4

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Different peptide fractions extracted from GVHD tissues were recognized by CTL generated against normal B/b spleen cells. B6 responders were primed intravenously with B/b spleen cells and restimulated in vitro with irradiated B/b spleen cells. The CTL obtained were incubated 4 h at an E : T = 50 : 1 with 51Cr-labelled RMA-S cells loaded with 20 µl HPLC fractions prepared from eluates of different tissues collected from irradiated B/b recipient grafted with B6 cells that developed a GVHD. Results are given as the percentage of specific lysis of peptide-loaded RMA-S cells.

CTL generation against normal and GVHD tissues

In the following experiments, we attempted to derive CTL against tissue-specific mHAgs by immunizing B6 mice with homogenized organs derived either from normal or from GVHD mice in order to compare the immunogenic capacity of solid tissues in normal and GVHD mice.

CTL that efficiently lysed B/b Con A blasts were generated only after two subcutaneous injections of homogenized normal or GVHD tissues emulsified into IFA and the intensity of the cytotoxic activity on B/b Con A blasts depended on the tissue used for immunization. Data presented in Fig. 5 represented the mean of three to six experiments. We found that the most immunogenic normal tissue was the kidney, inducing around 70% lysis, while others tissues ranged between 35% to 45% lysis at an E:T ratio of 50 : 1. Tissues collected from GVHD mice were less immunogenic than normal tissues (between 10% and 32% cytotoxicity at an E : T ratio of 50 : 1). The heart was particularly unable to elicit significant cytotoxicity. In addition, in vitro secondary stimulation with spleen cells collected from GVHD mice instead of normal mice resulted in very low cytotoxic activity (less than 12%) (data not shown).

Fig. 5.

Fig. 5

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Lytic activity of CTL generated against normal and GVHD tissues. B6 responders were primed subcutaneously in vivo with several normal or GVHD B/b homogenized tissues emulsified into IFA. Responding spleen cells were restimulated in vitro with irradiated B/b spleen cells. CTL generated were tested for their lytic capacity for 51Cr-labelled B/b ConA blast targets at different E : T ratios. ⋄, Normal; ▪, GVHD.

These organ-specific CTL raised against normal and GVHD tissues were compared for the repertoire of dominant peptides recognized in the eluates prepared from GVHD tissues (Fig. 6) and tested previously with CTL raised against normal spleen cells (Fig. 3). The same fractions prepared from kidneys were recognized regardless of whether CTL were generated against the normal or GVHD kidney. For all other tissues (spleen, skin and liver), a marked loss of detection of positive fractions occurred when CTL were raised against GVHD tissues instead of normal tissues. For instance, positivity of fraction 57 in the spleen, fraction 72 in the liver and fraction 28 in skin extracts disappeared. In contrast, CTL raised against GVHD skin strongly recognized fraction 73. These observations indicated a selective modification of mHAg immunogenicity that affected preferentially GVHD tissues.

Fig. 6.

Fig. 6

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Differential recognition of peptide fractions extracted from GVHD tissues by CTL generated against normal and GVHD B/b tissues. B6 responders were primed subcutaneously in vivo with several GVHD (upper part) or normal (lower part) B/b homogenized tissues emulsified into IFA. Responding spleen cells were restimulated in vitro with irradiated B/b spleen cells. The CTL obtained were incubated 4 h at an E : T = 50 : 1 with 51Cr-labelled RMA-S cells loaded with 20 µl HPLC fractions prepared from eluates of different tissues collected from irradiated B/b recipient grafted with B6 cells that developed a GVHD. Results are given as the percentage of specific lysis of peptide-loaded RMA-S cells. (a) CTL against normal tissues; (b) CTL against GVHD tissues.

Discussion

This paper examines the hierarchy of dominant mHAgs according to the tissue and the GVHD status of B/b mice transplanted with haematopoietic stem cells from H-2 compatible sex-matched B6 mice.

As dominance results from the complex interplay between the quantity of peptide-class I complexes expressed on APC and the repertoire of specific CD8+ CTL, we investigated first the expression of dominant mHAg peptides on tissues of normal and GVHD mice and secondly we compared the repertoire of CTL for dominant mHAgs generated by normal or GVHD tissues.

Global peptide elution from cell lysates and the use of bulk CTL were chosen to investigate mHAg expression in four GVHD target tissues (spleen, gut, liver and skin) and two control tissues (heart and kidney) as the B/b spleen CTL recognized mainly five HPLC fractions obtained from peptide eluates from the normal spleen, as already described by Nevala [26,27]. The pattern of dominant mHAg peptide expression was unique in each individual normal tissue and the intensity of some mHAg peptides varied considerably between tissues. Only two peptide fractions (28 and 62) were ubiquitously expressed and the three others (26, 56 and 72) showed tissue-specific expression. This is in accordance with the study of Griem [22] which showed, using specific T cell clones, that H4 minor antigens are expressed at different levels on the skin, small intestine, spleen and liver and not at all on the heart and kidney. Similar data were obtained for H-Y and mapki minor antigens [22]. Finally, a differential transcription of immunodominant mHAg peptides H-60 and H-28 has been reported in B/b mice compared to the B6 strain in professional APC [16,17]. Our results confirm the differential tissue distribution of mHAgs detected by bulk CTL, in an experimental situation close to human BMT.

When peptide eluates were prepared from the same six tissues collected from GVHD mice, the patterns of HPLC fractions recognized by the B6 anti-B/b spleen CTL also differed quantitatively and qualitatively from those obtained with peptide eluates prepared from normal mice. These changes could be the cumulative results of GVHD-induced cytokine release [23] that may increase the MHC class I molecule expression and modify the immunoproteasome activity.

The hierarchy of dominance also depends on the affinity between MHC class I peptide complexes and the T cell receptor of CTL responding to antigenic stimulation. In the first part of the study, CTL were generated by immunizing B6 mice with a viable suspension of spleen cells and in subsequent experiments solid organ preparations were used to generate CTL against the different tissues selected for peptide extraction. We found that immunogenicity is highly variable among the different normal tissues. These observations could be also related to different levels of MHC class I expression in these tissues. While the spleen, intestine (all cell types), skin (keratinocytes) and kidney display high class I molecule expression, the heart and liver (hepatocytes), display low normal expression [28] that could be enhanced in the GVHD condition. The tissue-dependency of mHAg expression also suggests that many of those could be missed in humans because peripheral blood mononuclear cells are preferentially used as targets in functional studies.

Some peptides were recognized by spleen-specific CTL when presented on RMA-S cells but were not able to elicit CTL when presented on solid organs. This observation also reflects qualitative and/or quantitative differences in peptide presentation as it is well documented that a lower peptide concentration is required for MHC peptide complex recognition compared to in vivo CTL priming. This could apply especially to the differences observed when CTL priming was performed with GVHD tissues instead of normal tissues (Fig. 6).

Altogether, these results obtained with bulk polyclonal CTL populations, thus reflecting as closely as possible the in vivo human situation, could have direct implications in allogeneic BMT. We showed that dominant mHAg peptides have a complex tissue distribution, that the hierarchy of dominant class I-restricted antigens differs from one tissue to another and that GVHD could affect tissue immunogenicity. The demonstration that a single immunodominant mHAg peptide could elicit a graft-vs.-leukaemia effect without causing GVHD [29] emphasizes further the need to define which combination of mHAg could trigger GVHD in the scope of future immune intervention.

Acknowledgments

We thank Simone Righenzi, Laurence Majbruch and Nicole Riché for their expert technical assistance in peptide preparation and testing. This work was supported by grants from the Association pour la Recherche contre le Cancer (ARC n°3012), the Fondation pour la Recherche Médicale (FRM ARS2000 2·03), EUROCORD III (QLRT–2001–01918) and EUROBANK (QLRI-CT–2000–00010).

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