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The Journal of Immunology, 1998, 161: 3808-3812.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Cross-Priming of CTL Responses In Vivo Does Not Require Antigenic Peptides in the Endoplasmic Reticulum of Immunizing Cells1

Stephen P. Schoenberger2, Ellen I. H. van der Voort, G. Menno Krietemeijer, Rienk Offringa, Cornelis J. M. Melief and Rene E. M. Toes

Department of Immunohematology and Blood Bank, University Hospital Leiden, Leiden, The Netherlands


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
It has been proposed that the cross-priming of CTL responses in vivo involves the transfer to host APCs of heat shock protein glycoprotein 96-chaperoned antigenic peptides released from the endoplasmic reticulum (ER) of dying or infected cells. We have tested this possibility directly using TAP-deficient cell lines lacking antigenic ER peptides derived from two model Ags, the human adenovirus type 5 early regions E1A and E1B. Although both proteins were well expressed, the cells were not recognized by E1A- or E1B-specific CTLs unless the relevant epitope was either provided exogenously as a synthetic peptide or targeted to the ER in a TAP-independent fashion. Despite the absence of these ER peptides, the TAP1-/- cells were able to efficiently cross-prime E1A- and E1B-specific CTLs following immunization of syngeneic mice. These results indicate that, although purified peptide/glycoprotein 96 complexes are potent immunogens, the mechanism of CTL cross-priming in vivo does not depend upon antigenic peptides in the ER of immunizing cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cross-priming refers to the uptake and MHC class I-restricted presentation of exogenous cell-associated Ag by professional host APCs that results in the activation of CTLs. Originally invoked as a mechanism to explain the ability of MHC-mismatched grafts to induce host MHC-restricted CTLs, the indirect presentation pathway is believed to play a critical role in immune surveillance and regulation by facilitating the transfer of Ags synthesized in nonhemopoetic tissues to lymphoid organs for presentation to naive T cells (1, 2). Recent evidence now indicates that, under certain circumstances, cross-presentation of self Ags from healthy tissues can also lead to deletion rather than activation of T cell responses in a process termed "cross-tolerance" (reviewed in ref. 3).

Although many details of the cross-priming pathway have been revealed, a central question remains the mechanism through which host APCs are able to introduce peptides derived from exogenous protein Ags into their own class I presentation pathway (4). A potential solution has emerged in the identification of a group of heat shock proteins (hsps)3 that are able to confer tumor-specific immunity through their association with antigenic peptides derived from intracellular proteins (5, 6, 7). The best-characterized and most immunogenic of these hsps, glycoprotein (gp)96, is an abundant component of the endoplasmic reticulum (ER) (8). In the ER, gp96 binds to TAP-transported peptides generated by cytosolic Ag processing (9, 10). In this capacity, gp96 can associate with a repertoire of antigenic peptides identical with the repertoire of proteins expressed inside the same cell.

Several lines of experimental evidence support a direct role for gp96 in the cross-priming of CTLs in vivo. First, immunization with gp96 purified from allogeneic tumor or virus-infected cells can elicit host MHC-restricted CTLs directed against the Ags expressed by the cells from which it was isolated (11, 12). This specific immunogenicity is lost when gp96 is stripped of bound peptides (7). Second, gp96 has been shown to endogenously associate with the same immunodominant vesicular stomatitis virus peptide in vesicular stomatitis virus-infected cells of different MHC types (13). Finally, a subset of macrophages has been shown to bind purified gp96 in vitro and direct the bound peptides into its own class I processing and presentation pathway (14). Based on these observations, Suto et al. proposed a mechanism of cross-priming in which the gp96-chaperoned peptides released by dying or infected cells bind to unknown receptors on the surface of macrophages (14). The complexes are then internalized, and the bound peptides are routed to the class I processing machinery of the macrophages for subsequent presentation to CTLs. This model of cross-priming is attractive because it not only preserves the logic of what type of Ags should be directed for presentation via MHC class I molecules but also identifies a host APC subset capable of transferring the exogenous gp96-peptide complexes to its own endogenous MHC class I presentation pathway.

Despite the numerous studies showing that gp96 purified from cells can prime CTL responses in vivo and the implicit logic of the proposed gp96-dependent cross-priming pathway, the relevance of gp96 to "classical" cross-priming involving cell-associated Ags has not been directly tested. In the present study, we have used immunization with TAP-deficient cells lacking defined ER peptides to determine whether the mechanism underlying in vivo cross-priming of CTL responses requires antigenic peptides in the ER of immunizing cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice and cell lines

TAP1-/- and wild-type (wt) TAP+/+ C57BL/6 mice were kindly provided by Dr. A. Berns of the Netherlands Cancer Institute. Murine embryo cells (MECs) expressing human adenovirus type 5 early region 1 (5E1) were generated as described previously (15). MECs expressing the SigE1A234–243 or pSigE1B192–200 minigenes were transfected by electroporation (Gene Pulser, Bio-Rad, Richmond, CA). The SigE1A234–243 plasmid has been described previously (16). The SigE1B192–200 plasmid was constructed by ligation of the duplex oligonucleotide 5'-GTAAATATCAGGAATTGTTGCTACATTTATAGTCCTTAACAACGA-3', encoding the E1B CTL epitope, into NotI/SwaI-digested pSPCV-DR2 (16).

Immunochemical detection of E1A and E1B proteins

Expression of E1A and E1B proteins was detected on cells fixed onto glass microscope slides using Abs specific for E1A (mAb M73A11) or E1B proteins (mAb A1C6) followed by a horseradish peroxidase-labeled second Ab (17, 18). Micrographs were taken on a Zeiss Axiophot light microscope (Carl Zeiss, Jena, Germany). Images were scanned and prepared using Adobe Photoshop (Adobe Systems, Mountain View, CA).

CTL recognition assays

Experimental procedures to measure cell-mediated lysis were performed using the chromium release assay as described elsewhere (19). For the TNF-secretion assay, 2 x 104 target cells were incubated in round-bottom 96-well plates with 2.5 x 103 CTLs in 150 µl of medium containing 10 Cetus units of rIL-2 (Cetus, Emeryville, CA). The supernatant was collected after 24 h, and its TNF content was determined by measuring its cytotoxicity on WEHI-164 clone 13 cells as described previously (20).

Immunizations and bulk CTL cultures

Groups of mice were immunized once with 1 x 107 irradiated (25 Gy) cells in 0.2 ml PBS. After 2 wk, splenocytes were harvested and cocultivated at 5 x 106 cells/well with 5E1-transformed stimulator cells at a ratio of 10:1 in 24-well plates. Following a 6-day coculture, viable lymphocytes were collected and tested for cytotoxicity on europium-labeled target cells as described previously (15).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In vitro transformation of TAP1-/- cells

To obtain cell lines lacking ER expression of antigenic peptides derived from nuclear and cytosolic proteins, MECs from TAP1-/- or wt (TAP+/+) mice were transfected with 5E1 encoding the E1A and E1B oncogenes. This yielded TAP1-/- 5E1-MECs and TAP+/+ 5E1-MECs, respectively. C57BL/6 (H-2b) MECs were chosen for transformation with 5E1 because they allow the use of H-2Db-restricted E1A- and E1B-specific CTL clones to test for the presence of antigenic peptides derived from these two independent Ags (15, 19). Both TAP-/- and TAP+/+ MECs were found to express low but detectable levels of surface H-2Db molecules (Fig. 1Go). Exposure to IFN-{gamma} up-regulated the surface Db expression on both TAP+/+ MECs and TAP+/+ 5E1-MECs. In contrast, surface Db expression on the TAP1-/- MECs and TAP-/- 5E1-MECs was not substantially increased following exposure to IFN-{gamma}, reflecting the absence of TAP-translocated peptides in the ER of these cells.



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  		FIGURE 1. Surface H-2Db levels on wt and TAP1-/- MECs. The surface levels of H-2Db molecules on wt TAP1+/+ MECs (A), TAP1+/+ 5E1-MECs (B), TAP1-/- MECs (C), or TAP1-/- 5E1-MECs (D) are depicted in a cytofluorometric analysis. Cells were cultured either in the presence (thick line) or absence (thin line) of 10 U/ml IFN-{gamma} for 48 h before staining with the H-2Db-specific mAb H1413110 followed by secondary staining with an FITC-conjugated anti-mouse Ab. The dotted line indicates the background fluorescence of cells stained with secondary Ab alone.

 
Although both the E1A and E1B proteins are abundantly expressed in both the TAP+/+ 5E1-MECs and TAP1-/- 5E1-MECs (Fig. 2Go), only the wt TAP+/+ 5E1-MECs are recognized by E1A- and E1B-specific CTL clones in a cytotoxicity assay (Fig. 3Go, A and B). The observed lack of recognition of the TAP1-/- 5E1-MECs is not due to resistance to CTL-mediated lysis, since these cells were lysed when pulsed exogenously with synthetic peptides corresponding to the E1A and E1B CTL epitopes (Fig. 3Go, A and B). This absence of recognition is also not due to the sensitivity differences in cloned vs short-term-cultured CTLs, because the TAP1-/- 5E1-MECs were not recognized by secondary bulk splenocytes from mice immunized with 5E1-MECs (data not shown). Similar results were also obtained in an alternative CTL assay in which the secretion of TNF by CTLs is used to determine CTL recognition (Fig. 3Go, C and D) (20). The TAP1-/- 5E1-MECs, in contrast to wt TAP+/+ 5E1-MECs, are not recognized by E1A- or E1B-specific CTLs. These results indicate that the TAP defect in the TAP1-/- 5E1-MECs prevents class I-restricted presentation of the endogenously synthesized E1A and E1B epitopes. To verify that lack of CTL recognition was due to the lack of 5E1-derived peptides in the ER and was not caused by defective assembly or by the ER-to-surface transport of peptide/MHC complexes, a signal sequence-containing minigene was used to target E1A or E1B epitope-containing peptides directly to the ER (21). Transfection of the TAP1-/- 5E1-MECs with either of these minigenes resulted in their recognition by the relevant CTLs (Fig. 3Go, C and D). This finding demonstrates that when antigenic peptides are provided to the ER, E1A and E1B epitope/MHC complexes are properly assembled and transported to the cell surface for recognition by CTLs. Taken together, these results indicate that the lack of TAP function in the TAP1-/- 5E1-MECs results in the absence of 5E1-derived antigenic peptides in the ER of these cells.



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  		FIGURE 2. Expression of E1A and E1B proteins by TAP1-/- 5E1-MECs. The expression of E1A (A and C) and E1B (B and D) proteins by TAP1-/- MECs (A and B) or 5E1-transformed TAP1-/- MECs (C and D) was detected by immunochemistry with specific Abs as described in Materials and Methods. Magnification = x400.

 


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  		FIGURE 3. Recognition of TAP1+/+ and TAP1-/- 5E1-MECs by specific CTLs. The recognition of IFN-{gamma}-treated (48-h) TAP1+/+ 5E1-MECs and TAP1-/- 5E1-MECs by E1A-specific (A and C) or E1B-specific CTLs (B and D) was tested in chromium release assays (A and B) or TNF-secretion assays (C and D) as described in Materials and Methods. Target cells were TAP1+/+ 5E1-MECs ({square}), TAP1-/- 5E1-MECs ({circ}), or TAP1-/- 5E1-MECs pulsed with either 5E1A234–243 peptide (•) or E1B192–200 peptide ({blacksquare}). SigE1A/TAP-5E1-MECs and SigE1B/TAP-5E1-MECs are transfectants of TAP1-/- 5E1-MECs as described in Materials and Methods. Peptide-pulsed targets were incubated with either E1A234–243 or E1B192–200 peptides for 30 min at 37°C before use as target cells.

 
Immunization with 5E1-TAP1-/- MECs induces E1A- and E1B-specific CTL responses

We subsequently investigated whether the lack of E1-derived peptides in the ER of immunizing cells would affect their capacity to induce E1A- and E1B-specific CTL responses in vivo. To this end, C57BL/6 mice were immunized with wt TAP+/+ 5E1-MECs or TAP1-/- 5E1-MECs. Bulk splenocyte cultures from mice immunized with wt TAP+/+ or TAP1-/- 5E1-MECs were tested for their ability to lyse 5E1-transformed target cells as well as MECs pulsed with the E1A and E1B peptides. Immunization with either TAP-/- or TAP+/+ 5E1-MECs induces a strong 5E1-specific CTL response to both the E1A and E1B epitopes (Fig. 4Go). These results demonstrate that the cross-priming of MHC class I-restricted CTL responses does not require antigenic peptides in the ER of immunizing cells.



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  		FIGURE 4. Immunization with TAP1+/+ 5E1-MECs and TAP1-/- 5E1-MECs induces E1-specific CTLs. C57BL/6 mice were immunized s.c. with either 107 TAP+/+ 5E1-MECs (A and C) or TAP1-/- 5E1-MECs (B and D) in 0.2 ml PBS. After 2 wk, splenocytes were restimulated in vitro with either SigE1A234–243 MECs (15) (A and B) to specifically restimulate the quantitatively weaker E1A CTL response (18) or with TAP1+/+ 5E1-MECs (C and D) to restimulate E1B-specific CTL responses. After a 6-day coculture, the lytic activity of the bulk splenocytes was tested against the following target cells: TAP1+/+ 5E1-MECs ({square}) or TAP1+/+ MECs pulsed with either E1A234–243 peptide ({circ}) or E1B192–200 peptide (•). The percent specific lysis at various E:T ratios is depicted.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results demonstrate that in vivo cross-priming of MHC class I-restricted CTL responses against cell-associated Ags does not require TAP-transported peptides in the ER of immunizing cells. Both the TAP+/+ and TAP-/- MECs used in our study clearly show intracellular expression of both the E1A and E1B proteins (Fig. 2Go); however, only the TAP+/+ 5E1-MECs were recognized by E1A- or E1B-specific CTLs. CTL recognition of the TAP1-/- 5E1-MECs could be restored by exogenous addition of synthetic peptides comprising the E1A and E1B epitopes (Fig. 3Go, A and B). As CTL triggering is thought to require very few peptide/MHC complexes, the lack of CTL recognition indicates the absence of surface MHC class I molecules containing E1A- and E1B-derived antigenic peptides (22). The fact that the TAP1-/- 5E1-MECs are recognized by CTLs when longer peptides containing the E1A or E1B epitopes were provided directly to the ER in a TAP-independent fashion (Fig. 3Go, C and D) confirms that the recognition defect lies in the absence of 5E1-derived antigenic peptides in the ER of these cells. Nevertheless, the TAP1-/- 5E1-MECs are able to efficiently cross-prime E1A- and E1B-specific CTL responses in vivo, demonstrating that the mechanism of cross-priming does not depend upon the presence of peptides in the ER of immunizing cells as a source of Ag for transfer to host APCs.

These findings are relevant for understanding the physiologic role of peptide-binding ER proteins such as gp96 in cross-priming. As mentioned previously, a cross-priming pathway that operates via the transfer of ER peptides from immunizing cells to host APCs would simplify the "choices" faced by APCs concerning whether a given phagocytosed Ag should be shunted to the MHC class I vs class II pathways. It would be of no obvious advantage for the APCs to present all phagocytosed material via class I, as only a subset of these antigenic complexes would be likely to be encountered on target cells in the periphery. A gp96-dependent cross-priming pathway would solve this problem by focusing CTL responses to antigenic peptides that are destined for loading onto class I molecules of target cells. Although purified gp96 preparations, like many cell-derived immunogens, can clearly be used to immunize for specific CTL responses, our data show that gp96 does not represent an essential component of the in vivo cross-priming pathway for cell-associated Ag.

The immunogenicity of gp96 preparations was first revealed by experiments which used cell fractionation to identify Ag(s) underlying the ability of tumor-cell vaccination to confer protective immunity (5). Following the challenge of mice immunized with specific cellular fractions, it was found that the tumor-derived gp96 (bound to tumor peptides) alone could confer protective immunity. This observation led to the notion that the gp96/peptide complexes mediated the immunogenicity of the tumor cells (5, 23). However, the possibility exists that the experimental approach used in these studies may have biased the outcome of the immunizations. Whereas certain synthetic peptides are able to prime CTLs without adjuvants, injection of soluble protein does not generally induce CTL responses (24). When offered as an exogenous Ag without adjuvants, the only tumor-derived cellular fraction able to induce class I-restricted tumor-specific CTLs would likely have to be either a peptide or a peptide chaperone such as gp96. This view suggests that the mechanism for induction of protective immunity by tumor cell vaccination may not be the same as that elicited by immunization with purified gp96. Our present results support and extend this idea by showing that tumor cells in which antigenic peptides do not reach the ER, and therefore cannot endogenously associate with gp96, are nevertheless able to efficiently cross-prime CTL responses. Although we cannot formally exclude the possibility that the E1-derived antigenic peptides were able to associate with gp96 in the cytoplasm or extracellular environment when released from the dying TAP-/- cells, this option is considered unlikely in light of the recent report indicating that gp96 isolated from TAP-defective cells did not associate with antigenic peptides following lysis of these cells in vitro (9). Based on these results, we conclude that peptide-binding ER proteins such as gp96 or those described recently by others do not comprise essential components of the Ag-transfer mechanism operative in in vivo cross-priming (9, 25, 26).

The mode of transfer of antigenic material from immunizing cells to host APCs during cross-priming remains a compelling question with important implications for the induction of CTL responses through specific vaccination. As noted by Bevan, particulate Ag in the form of damaged cells would effectively limit the wide range of endocytosed Ags to those best shunted to the class I pathway for presentation to CTLs (27). Recent evidence for the shedding of antigenic vesicles, the release of apoptotic blebs from cells, or their apparent transfer to dendritic cells in vitro raises interesting possibilities with regard to how cell-associated Ags are obtained by APCs (28, 29, 30). Our results do not argue against the possibility that other hsps, such as hsp70, may play a direct role in Ag transfer to APCs. A clearer understanding of the mechanism underlying cross-presentation of Ags to CTLs is an important goal toward the development of more effective methods of inducing immunity against tumors and infectious agents as well as controlling the pathologic effects of autoimmunity.


   Acknowledgments
 
We thank Dr. Frits Koning for critical evaluation of the manuscript and Dr. Stephen S. Wilson and Jan Beentjes for assistance in preparing the photomicrographs.


   Footnotes
 
1 This work was funded by grants from the Dutch Cancer Society and the European Community. The research of R.E.M.T. has been made possible by a fellowship of the Royal Netherlands Academy of Arts and Sciences. Back

2 Address correspondence and reprint requests to Dr. Stephen P. Schoenberger, Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121. E-mail address: Back

3 Abbreviations used in this paper: hsp, heat shock protein; gp, glycoprotein; ER, endoplasmic reticulum; MEC, murine embryo cell; E1, early region 1; 5E1, human adenovirus type 5 E1; wt, wild-type. Back

Received for publication June 25, 1998. Accepted for publication August 10, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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