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The Journal of Immunology, 2001, 166: 4968-4972.
Copyright © 2001 by The American Association of Immunologists

Adjuvanticity of {alpha}2-Macroglobulin, an Independent Ligand for the Heat Shock Protein Receptor CD911

Robert J. Binder, David Karimeddini and Pramod K. Srivastava2

Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06030


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We recently have identified CD91 as a receptor for the heat shock protein gp96. CD91 was identified initially as a receptor for {alpha}2-macroglobulin ({alpha}2M). Gp96 and {alpha}2M are both ligands for CD91. Because gp96-chaperoned peptides can prime CD8+ T cell responses and are re-presented by APCs, we tested {alpha}2M for similar properties. Our studies show that {alpha}2M binds peptides in vitro and that the peptides, chaperoned by {alpha}2M, efficiently prime peptide-specific CD8+ T cell responses in mice immunized with {alpha}2M-peptide complexes. Furthermore, peptides chaperoned by {alpha}2M, like those chaperoned by gp96, can be re-presented by CD91+ APCs on their MHC I molecules. These studies demonstrate that {alpha}2M molecules, like the heat shock protein molecules, are T cell adjuvants that can channel exogenous Ags into the endogenous pathway of Ag presentaion. The remarkable similarities between an intracellular chaperone and an extracellular serum chaperone may have interesting physiological ramifications.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Heat shock proteins (HSPs)3 are abundant intracellular proteins present in all cells. A subset of HSPs such as gp96, hsp90, hsp70, and calreticulin possess unique immunological properties (1): they bind a broad array of peptides, and immunization with the HSP-peptide complexes is highly effective at eliciting potent peptide-specific, MHC I-restricted, CTL responses. For this reason, the HSPs, although of mammalian ori-gin, are potent T cell adjuvants (2). Surprisingly small quantities of peptides, e.g., tens of picograms, if complexed to HSPs are sufficient to elicit CTL responses (2), and immunization with HSP-peptide complexes is very sensitive to abrogation of APCs of the immunized host (3). These observations had led us to propose in 1993 that HSPs interact with APCs through specific receptors, which are responsible for their anomalous and potent immunological properties (4). It was subsequently demonstrated that gp96-peptide complexes are taken up by APCs and the gp96-chaperoned peptide, after internal processing in the APC, is re-presented on the MHC I molecule of the APC (5). A cell surface receptor for the HSP gp96, expressed on APCs, has indeed been identified recently as CD91 or {alpha}2-macroglobulin ({alpha}2M) receptor (6). Gp96, with its chaperoned peptides, binds this receptor, allowing for its internalization and for the re-presentation of the chaperoned peptides. mAbs to CD91 inhibit such re-presentation by gp96, as do other ligands for CD91, such as {alpha}2M. {alpha}2M is a serum protein that has some chaperone-like properties. It binds a wide array of molecules such as cytokines and proteinases and internalizes them through its receptor CD91 (7). Because gp96 and {alpha}2M appear to bind to the same receptor, CD91, we have asked the question whether {alpha}2M, like gp96, can bind peptides, whether {alpha}2M-peptide complexes, like gp96-peptide complexes, can elicit peptide-specific CTL responses, and whether {alpha}2M-peptide complexes, like gp96-peptide complexes, can be re-presented by APCs.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell lines and reagents

RAW264.7 was a gift from C. Nicchitta (Duke University, Durham, NC), and RAW309Cr.1 was purchased from American Type Culture Collection (Manassas, VA). Peritoneal exudate cells (PEC) were obtained from the peritoneum of BALB/c or C57BL/6 mice (The Jackson Laboratory, Bar Harbor, ME) by flushing with cold PBS. Peptides AH1–20 and OVA20 were synthesized at Genemed Synthesis (San Francisco, CA). AH1–20 refers to a 20-mer extended variant (NH2-RVTYHSPSYVYHQFERRAK-COOH) of the Ld-binding epitope AH1 (NH2-SPSYVYHQF-COOH) of the CT26 mouse colon carcinoma (8). OVA20 refers to a 20-mer extended variant (NH2-SGLEQLESIINFEKLTEWTS-COOH) of the Kb-binding epitope OVA8 (SIINFEKL) of OVA (9). CT26 and OVA-expressing E.G7 cells (10) were obtained from our cell culture bank.

Iodination of peptides

This was conducted by using IODO-BEADS (Pierce, Rockford, IL) as per the manufacturers protocol. Free 125I was removed by using kwik-sep gel filtration columns (Pierce) as per the manufacturers protocol.

Flow cytometry

Flow cytometry was performed on a FACScan (Becton Dickinson, San Jose, CA). For FACScan analysis, all cells were incubated with Fc-BLOCK (anti-CD16/32 Ab) purchased from BD PharMingen (San Diego, CA). Rabbit anti-mouse CD91 polyclonal IgG was generated in our laboratory and has been described previously (6). The CD11b Ab was purchased from BD PharMingen. Isotype control rabbit IgG and isotype control rat IgG were used for the anti-CD91 and anti-CD11b Abs, respectively.

Purification of gp96 and peptide complexing

Gp96 was purified as published previously (11). {alpha}2M and serum albumin (SA) were purchased from Sigma (St. Louis, MO). Peptides were incubated with proteins at a 50:1 molar ratio and incubated at 50°C for 10 min followed by a 30-min incubation at 25°C. Free (uncomplexed) peptides were removed by size-exclusion filters (Millipore, Bedford, MA). Protein-peptide complexes were measured in a scintillation counter and per molar basis, each protein was observed to bind equivalent amounts of peptide (~0.1% of the starting amount of the peptide). Protein-peptide complexes were stored at 4°C until use.

Re-presentation assays

Re-presentation assays were performed as described previously (6). Briefly, 1 x 104 T cells were incubated with 1 x 104 of the indicated APC. The indicated protein (40 µg/ml), with or without bound peptide (as described in the previous section), was added to the cultures. As controls, the extended peptides or the precise MHC I epitopes were added at 1 µM final concentration. Culture supernatants were harvested after 20 h and assayed for IFN-{gamma} by ELISA with kits purchased from Endogen (Woburn, MA) and used according to the manufacturers protocol.

Immunizations and mixed lymphocyte tumor cell cultures

BALB/c or C57BL/6 mice were immunized with the peptides AH1–20 or OVA20, respectively, alone or complexed to {alpha}2M, gp96, or albumin (50 µg of each protein in 100 µl of PBS). Immunizations were performed i.p. Mice were boosted with 50 µg of the same complex after 1 wk. Spleen cells were removed 1 wk after the last immunization and cultured with irradiated stimulator cells, the AH1-expressing CT26 cells line, or the OVA-expressing cell line EG7. Cultures were tested for the presence of CTL in a 51Cr release assay by using AH1-pulsed or SIINFEKL-pulsed target cells, respectively.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
{alpha}2M, gp96, and SA bind antigenic peptides in vitro

Gp96 and SA have been shown previously to bind peptides in vitro by coincubation of proteins and peptides at 50°C (2). We tested whether {alpha}2M could bind peptides under similar conditions. Gp96, {alpha}2M, and SA were mixed with iodinated preparations of AH1–20 peptide (described in Materials and Methods) for 30 min at 50°C and the mixtures were analyzed by SDS-PAGE (to detect the proteins) and autoradiography (to detect bound peptides). All three proteins were seen to bind peptides (Fig. 1GoA) and the protein-peptide interaction was observed to be stable under denaturing SDS-PAGE. This has been observed previously (2) for gp96 and SA and was now observed for {alpha}2M as well. Similar data was obtained with the OVA20 peptide (data not shown).



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  		FIGURE 1. {alpha}2M, gp96, and SA bind peptides in vitro. A, {alpha}2M, gp96, or SA were incubated with 125I-labeled AH1–20 peptide at 50°C for 10 min followed by a 30-min incubation at 25°C. Free peptide was removed as described in Materials and Methods. Protein-peptide complexes were analyzed on a 5–15% gradient SDS-PAGE (top). Gels were exposed to film and autoradiographed (bottom). B, {alpha}2M or SA (1 µg) were incubated with increasing quantities of 125I-labeled AH1–20 peptide at 37°C. For SA, only the reaction with the highest quantity of peptide is shown. All other experimental conditions are the same as in A. The binding was measured as in A. Top panels are the autoradiographs of the silver-stained gels (bottom).

 
Binding at 50°C is obviously an experimentally created artifactual condition. We tested the binding of peptides to {alpha}2M and SA at 37°C as well. The experimental conditions and assays described above were used except that the binding reaction was conducted at 37°C. Titrated quantities of the peptide AH1–20 were used in binding to {alpha}2M or to SA. It was observed that AH1–20 bound to {alpha}2M but not SA in a dose-dependent and saturable manner (Fig. 1GoB).

Antigenic peptides chaperoned by {alpha}2M elicit a CD8+ T cell response

Gp96-peptide and {alpha}2M-peptide complexes were generated with AH1–20 and OVA20, and the preparations were filtered through size exclusion filters to remove free peptides. Mice were immunized i.p. twice, 1 wk apart, with 50 µg of each complex in PBS, per immunization. Control mice were immunized with 1 µg of peptide alone (uncomplexed). Spleen cells were removed 1 wk after the last immunization and incubated in vitro with irradiated stimulator cells (CT26 or E.G7, respectively) for 1 wk. Cytotoxic assays were performed on the cultures by using P815 (H-2d) cells pulsed with AH1 or EL4 cells (H-2b) pulsed with SIINFEKL as indicated in Fig. 2Go. Complexes of AH1–20 or OVA20 with {alpha}2M or gp96 were able to prime an AH1-specific CTL response in BALB/c immunized mice or an OVA8-specific CTL response in C57BL/6 mice, respectively (Fig. 2Go). Either peptide complexed with SA did not elicit a CTL response, as observed previously (2), nor did mice immunized with peptide alone, protein alone (uncomplexed to peptide), or with PBS.



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  		FIGURE 2. {alpha}2M-peptide complexes prime a peptide-specific CD8+ T cell response. BALB/c (top) or C57BL/6 (bottom) mice were immunized twice, 1 wk apart, with AH1–20 (top) or OVA20 (bottom) peptides uncomplexed (free) or complexed to {alpha}2M, gp96, or SA or with PBS as indicated. Spleen cells were stimulated with irradiated CT26 (top) or E.G7 (bottom) for 1 wk before testing for cytotoxicity against AH1- (top) or SIINFEKL- (bottom) pulsed target cells, as indicated. Three mice per group were immunized; data is shown for a representative mouse. The experiment was performed in duplicate.

 
Peptides chaperoned by {alpha}2M are re-presented by CD91-expressing APCs

{alpha}2M-peptide complexes, and as controls, gp96-peptide complexes and SA-peptide complexes, were tested in a re-presentation assay. We chose three types of APCs for the re-presentation: the macrophage cell line RAW264.7 and CD11b+ PEC, both of which express high levels of the gp96-receptor CD91; and the macrophage cell line RAW309Cr.1, which expresses little or no CD91 (Fig. 3GoA).



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  		FIGURE 3. CD91-expressing APC can re-present peptides chaperoned by {alpha}2M or gp96. A, RAW264.7 and CD11b+ PEC express significant levels of CD91 but RAW309Cr.1 does not. RAW264.7, RAW309Cr.1, and PEC were stained with anti-CD91 and anti-CD11b Abs. RAW264.7 cells also were stained with isotype control Abs (first panel on left); rabbit IgG and rat IgG, respectively. B, RAW264.7 cells (top) or RAW309Cr.1 cells (bottom) were used as APCs for re-presentation of complexes of {alpha}2M, gp96, or SA with AH1–20, to AH1-specific T cells. Release of IFN {gamma} was monitored as a marker of T cell stimulation. The contents of each well are indicated. Each well was tested in duplicates and the experiment was repeated three times. C, CD11b+ PECs from C57BL/6 mice were used as APCs for re-presentation of complexes of {alpha}2M, gp96, or SA with OVA20 to SIINFEKL-specific T cells. Release of IFN-{gamma} was monitored as a marker of T cell stimulation. The contents of each well are indicated. Each well was tested in duplicates and the experiment was repeated three times.

 
The Ld-restricted epitope AH1 (derived from the gp70 Ag of murine colon carcinoma CT26, as described in Materials and Methods) was used as the first model system. Complexes of {alpha}2M, gp96, or SA with an AH1–20 peptide (designed to inhibit direct charging of surface Ld of the APC by AH1) were pulsed onto RAW264.7 cells that were used to stimulate a Ld/AH-1-specific CD8+ T cell clone. As shown in Fig. 3GoB, T cells were stimulated by the re-presenting APC and secreted IFN-{gamma}. Control APCs pulsed with {alpha}2M or gp96 without AH1–20 did not stimulate T cells. The CD91-nonbinding protein SA, which binds effectively to peptides (Fig. 1Go), did not stimulate T cells when pulsed onto APC at any concentration tested. When the same experiment was repeated with the CD91-negative APC, RAW309Cr.1, no re-presentation of either gp96-chaperoned peptides or of {alpha}2M-chaperoned peptides was detected.

In a second system, complexes of {alpha}2M, gp96 or SA with SIINFEKL (OVA8)-precursor OVA20 were pulsed onto CD11b+ cells (purified from PEC). These pulsed APCs were used to stimulate the Kb/SIINFEKL-specific CD8+ T cell clone, 4G3. As shown in Fig. 3GoC, 4G3 T cells secreted IFN-{gamma} in response to APC pulsed with gp96-OVA20 or {alpha}2M-OVA20 complexes but not with SA-OVA20 complexes. The control wells that lacked OVA20 did not show re-presentation (Fig. 3GoC).

We next compared the efficiency of re-presentation of peptides chaperoned by gp96 and {alpha}2M. Equivalent molar amounts of gp96 and {alpha}2M, complexed to AH1–20, were pulsed onto RAW264.7 cells. Pulsed APCs were used to stimulate AH1-specific T cells, and the amount of T cell stimulation (as monitored by IFN-{gamma} release) was measured. Fig. 4Go shows that on a molar basis, the gp96-peptide complexes are re-presented with a slightly higher efficiency than the {alpha}2M-peptide complexes, even though both molecules chaperone approximately equal amount of peptides. The differences in efficiency is more clearly seen at the lower concentrations, where gp96-chaperoned peptides are re-presented 1.8 times more efficiently than peptides chaperoned by {alpha}2M. As noted in the legend to Fig. 4Go, peptides chaperoned by SA were not re-presented, even at very high molar concentrations.



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  		FIGURE 4. Gp96-chaperoned peptides are re-presented arguably more efficiently than {alpha}2M-chaperoned peptides. RAW264.7 cells were pulsed with increasing molar quantities of {alpha}2M-AH1–20, gp96-AH1–20, or SA-AH1–20 complexes. Pulsed APCs were used to stimulate the AH1-specific T cell clone as in Fig. 2Go. IFN-{gamma} release was measured as an index of stimulation. The background of the experiment was ~10% of the signal and is subtracted from all numbers. The experiment was performed in duplicate. Data for SA-AH1–20 were at the baseline and are not shown.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our studies show that {alpha}2M can bind peptides in vitro. In its SDS stability, quantity, and temperature sensitivity, this binding appears to be qualitatively similar to that observed for gp96 as reported previously (2). {alpha}2M is known to bind a wide array of cytokines and proteases by an unusual mechanism, and it is conceivable that the peptide-binding observed here recapitulates that mechanism (7). {alpha}2M-Ag complexes have been demonstrated previously to elicit a strong Ab response (12, 13) and a CD4+ T cell response (14) after sequestration by APCs. These responses are to be expected of an exogenous Ag. The novelty of our studies lies in the demonstration that despite exogenous administration, {alpha}2M-Ag complexes, like HSP-peptide complexes, elicit, a peptide-specific, CD8+ T cell response.

The re-presentation of {alpha}2M-chaperoned peptides, as observed here, provides mechanistic insight into the adjuvanticity of {alpha}2M. It appears that CD91 is central to this adjuvanticity: peptide-binding proteins like gp96 and {alpha}2M that bind CD91 can have their peptides re-presented on MHC I, whereas those like SA that do not bind CD91 do not. Conversely, APCs that express CD91 can re-present gp96-chaperoned and {alpha}2M-chaperoned peptides, whereas CD91-negative APCs cannot. CD91 seems to be a unique portal into the APC that allows entry of the materials through it, a special opportunity of entering the endosomal-cytosolic compartment. This should be a promising area of cell biological investigation.

During identification of CD91 as the receptor for gp96, we proposed a model (6) in which {alpha}2M samples the extracellular milieu and the HSPs the intracellular milieu: altogether, the CD91 molecule becomes a mechanism for the APC to sample the entire antigenic milieu of an organism. The new and remarkable similarities between intracellular chaperones (HSPs) and an extracellular serum chaperone ({alpha}2M) observed by us here lead us to strengthen our faith in that model and to ask whether the unusual protein-trapping mechanism, so unique for {alpha}2M, is indeed primarily an Ag sampling device par excellence. These ideas may have some bearing on immune response to cancers and infectious diseases and on mechanisms of peripheral tolerance.


   Acknowledgments
 
We thank Sreyashi Basu, Toyoshi Matsutake, and Thirumalai Ramalingham of our laboratory for critically reading the manuscript. We also thank Maria Bausero for technical support in some of the experiments.


   Footnotes
 
1 This work was supported by National Institutes of Health Grant CA84479 and a research agreement with Antigenics, Inc., in which P.K.S. has a significant financial interest. Back

2 Address correspondence and reprint requests to Pramod Srivastava, University of Connecticut School of Medicine, MC1601, Farmington, CT 06030-1920. Back

3 Abbreviations used in this paper: HSP, heat shock proteins; {alpha}2M, {alpha}2-macroglobulin; PEC, peritoneal exudate cells; SA, serum albumin. Back

Received for publication December 1, 2000. Accepted for publication February 6, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Srivastava, P. K., A. Menoret, S. Basu, R. J. Binder, K. L. McQuade. 1998. Heat shock proteins come of age: primitive functions acquire new roles in an adaptive world. Immunity 8:1.[Medline]
  2. Blachere, N. E., Z. Li, R. Y. Chandawarkar, R. Suto, N. S. Jaikaria, S. Basu, H. Udono, P. K. Srivastava. 1997. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J. Exp. Med. 186:1315.[Abstract/Free Full Text]
  3. Udono, H., D. L. Levey, P. K. Srivastava. 1994. Cellular requirements for tumor-specific immunity elicited by heat shock proteins: tumor rejection antigen gp96 primes CD8+ T cells in vivo. Proc. Natl. Acad. Sci. USA 91:3077.[Abstract/Free Full Text]
  4. Srivastava, P. K., H. Udono, N. E. Blachere, Z. Li. 1994. Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics 39:93.[Medline]
  5. Suto, R., P. K. Srivastava. 1995. A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 269:1585.[Abstract/Free Full Text]
  6. Binder, R. J., D. K. Han, P. K. Srivastava. 2000. CD91: a receptor for heat shock protein gp96. Nat. Immunol. 1:151.[Medline]
  7. Aschom, J. D., S. E. Tiller, K. Dickerson, J. L. Cravens, W. S. Argraves, D. K. Strickland. 1990. The human {alpha}2-macroglobulin receptor: identification of a 420-kD cell surface glycoprotein specific for the activated conformation of {alpha}2-macroglobulin. J. Cell Biol. 110:1041.[Abstract/Free Full Text]
  8. Huang, A. Y., P. H. Gulden, A. S. Woods, M. C. Thomas, C. D. Tong, W. Wang, V. H. Engelhard, G. Pasternack, R. Cotter, D. Hunt, D. M. Pardoll, E. M. Jaffee. 1996. The immunodominant major histocompatibility complex class I-restricted antigen of a murine colon tumor derives from an endogenous retroviral gene product. Proc. Natl. Acad. Sci. USA 93:9730.[Abstract/Free Full Text]
  9. Rotzschke, O., K. Falk, S. Stevanovic, G. Jung, P. Walden, H.-G. Rammensee. 1991. Exact prediction of a natural T cell epitope. Eur. J. Immunol. 21:2891.[Medline]
  10. Moore, M. W., F. R. Carbone, M. J. Bevan. 1988. Introduction of soluble protein into the class I pathway of antigen processing and presentation. Cell 54:777.[Medline]
  11. Srivastava, P. K.. 1997. Purification of heat shock protein-peptide complexes for use in vaccination against cancers and intracellular pathogens. I. Lefkovits, ed. Immunology Methods Manual 739. Academic Press, London.
  12. Mitsuda, S., T. Nakagawa, T. Osada, A. Ikai. 1993. A receptor-mediated antigen delivery and incorporation system: administration of {alpha}2-macroglobulin-cytochrome c conjugate induced high concentrations of antibodies against cytochrome c in mice. Biochem. Biophys. Res. Commun. 191:1326.[Medline]
  13. Chu, C. T., T. D. Oury, J. J. Enghild, S. V. Pizzo. 1994. Adjuvant-free in vivo targeting: antigen delivery by {alpha}2-macroglobulin enhances antibody formation. J. Immunol. 152:1538.[Abstract]
  14. Chu, C. T., S. V. Pizzo. 1993. Receptor-mediated antigen delivery into macrophages: complexing antigen to {alpha}2-macroglobulin enhances presentation to T cells. J. Immunol. 150:48.[Abstract]



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