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Original Article |
mbevan{at}u.washington.edu
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Key Words: major histocompatibility complex class I • antigen presentation • antigen-presenting cell • cytotoxic T lymphocyte • cross-priming
Bone marrow chimera studies demonstrated that the ability to cross-present cell-associated antigens is restricted to bone marrow–derived APCs 410. Several groups have investigated the role of macrophages and dendritic cells (DCs) in presenting exogenously derived antigens in MHC class I in vitro (for a review, see reference 7). Exogenous antigens in the form of soluble proteins, particulate antigens, and cell-associated antigens derived from apoptotic or necrotic cells have been shown to be taken up, processed, and presented to CD8+ T cells by both cell types 11121314151617. Other reports have indicated that cross-presentation is a specific property of DCs 181920. However, which bone marrow–derived APC is involved in MHC class I–restricted presentation of exogenous antigens in vivo has not been examined.
DCs comprise populations of cells with heterogeneous phenotypes 2122. Murine splenic DCs can be divided into two subsets, both of which express high levels of CD11c. One DC population is further characterized by high expression of the myeloid marker CD11b and by absence of expression of CD8
In addition to phenotypic differences, the lymphoid and myeloid DCs reside in different areas of the spleen. Whereas lymphoid DCs are localized in the T cell–rich areas of the periarteriolar lymphatic sheaths (PALS), myeloid DCs can be found in the marginal zone 2136. Functional distinctions between lymphoid and myeloid DCs have also been reported. Initial in vitro studies indicated that lymphoid DCs could suppress T cell responses by causing apoptosis of CD4+ T cells and by limiting IL-2 production by CD8+ T cells, whereas myeloid DCs were shown to be strong stimulators of primary T cell responses 3738. These findings led to the suggestion that myeloid and lymphoid DCs function as T cell stimulators and tolerizers, respectively. However, in a recent study, peptide-coated DCs of both subsets were shown to induce strong CD8+ T cell responses, indicating no inherent tolerizing function for lymphoid DCs 39. Both DC subsets do appear to differ in their ability to activate CD4+ cells, as myeloid DCs preferentially stimulate Th2 responses, whereas lymphoid DCs preferentially induce Th1 responses 404142. The role of both DC subsets in cross-priming of CD8+ T cells in vivo has not been investigated.
To determine the cell types responsible for cross-priming in vivo, we primed C57BL/6 (B6) mice with irradiated, β2-microglobulin–/– (β2m–/–) splenocytes loaded with OVA in their cytoplasm. Such β2m–/– splenocytes are unable to present the OVA epitope in association with MHC class I molecules, but they elicit, when injected in B6 mice, OVA-specific, MHC class I–restricted CTL responses. We show that host splenic DCs take up and present cell-associated OVA to CD8+ T cells. Analysis of the OVA-presenting DCs indicated that only lymphoid DCs, and not myeloid DCs, cross-present antigens in vivo. This result points to an important and distinct role for lymphoid DCs in the generation of CD8 T cell responses directed towards cell-associated antigens.
Antibodies.
Cross-priming with OVA-loaded β2m–/– Cells.
CFSE Labeling of OT-I Cells.
Low Density Cell Preparation.
Magnetic Bead Depletion.
Proliferation Assay.
Introduction
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Abstract
Introduction
Materials and Methods
Results
Discussion
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Naive CD8+ T cells are stimulated to proliferate and to develop into cytotoxic effector T cells after recognition of short peptides associated with MHC class I molecules on professional APCs. "Endogenous" cytosolic proteins are generally the source of MHC class I–restricted antigens. These proteins are degraded by the proteasome, and peptides are transported to the endoplasmic reticulum by the transporter associated with antigen presentation (TAP) transporter, where they can bind to newly synthesized MHC class I molecules. In contrast, membrane-associated proteins and endocytosed "exogenous" proteins are mainly presented by MHC class II molecules for recognition by CD4+ T cells. However, the division of the endogenous and exogenous pathway is not absolute. 25 years ago, it was recognized that immunization with cells lacking host MHC alleles, but bearing foreign minor histocompatibility antigens, leads to minor specific CD8+ T cell activation that is restricted to the host MHC allele 12. This suggested that host APCs can process exogenous cell-associated antigens and present them in the context of MHC class I molecules, a process termed cross-priming or cross-presentation. Since then, cross-priming has been shown to be important in initiating MHC class I–restricted responses to tumors, peripheral self, viral, and bacterial antigens 3456. This indicates that cross-presentation is a general mechanism for the induction of T cells specific for antigens not expressed by APCs themselves and is involved in a variety of T cell responses 7. In addition to T cell activation, cross-presentation has been shown to induce T cell tolerance 89. 
and DEC-205, whereas the other is CD11blowCD8+DEC-205+ 2324252627. The CD8–CD11bhigh DCs can be further divided into a CD4+ and CD4– population 28. Some evidence suggests that the CD8+ and CD8– DC subsets belong to different lineages. Several transcription factor knockout and mutant mice exhibited differential effects on the development of each subset in vivo 29303132. In addition, CD8+ DCs were shown to be derived from a thymic progenitor that could not generate myeloid cells, whereas CD8– DCs can be grown from bone marrow using GM-CSF 333435. Therefore, CD8+ DCs are thought to relate to the lymphoid lineage, whereas CD8– DCs are considered myeloid related. For convenience, in this paper we will use the terms lymphoid DC and myeloid DC to describe the CD8+ and CD8– DC subsets.
Materials and Methods
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Materials and Methods
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Mice.
β2m–/– and B6 mice were purchased from Taconic Farms. OT-I recombination-activating gene (RAG)2–/– and Thy1.1+ OT-I mice were bred in our specific pathogen-free facility and have a transgenic V2Vβ5 TCR specific for the OVA257–264 epitope in the context of H2-Kb 43.
CD11c-, CD11b-, CD8-, CD8β-, Kb/Db-, and I-Ab–specific antibodies were purchased from BD PharMingen. Biotinylated DEC-205–specific antibodies were a gift from A. Rudensky (University of Washington, Seattle, WA). Flow cytometry was conducted on a FACSCaliburTM and analyzed using CELLQuestTM software (Becton Dickinson). Cell sorting was performed in HBSS with 25 mM Hepes using a FACS VantageTM (Becton Dickinson).
Single cell suspensions were prepared in serum-free medium from spleen and cervical, axillary, brachial, inguinal, and mesenteric lymph nodes from female β2m–/– mice. Cells were loaded with OVA by osmotic shock as described previously 44. In short, 
15 x 107 cells were incubated in 1 ml of hypertonic medium (0.5 M sucrose, 10% wt/vol polyethylene glycol 1000, and 10 mM Hepes in RPMI 1640, pH 7.2) containing 10 mg/ml OVA (Calbiochem) for 10 min at 37°C. 13 ml of prewarmed hypotonic medium (40% H2O, 60% RPMI 1640) was added and the cells were incubated for an additional 2 min at 37°C. The cells were centrifuged, washed twice with cold PBS, and irradiated (1,350 rads). 20–35 x 106 OVA-loaded cells were injected in 200 µl of PBS into the tail vein. In one experiment, β2m–/– cells were shocked with both OVA and yellow/green fluorescent 0.2 µm beads (Molecular Probes). The beads were washed two times in PBS by centrifugation for 10 min at 1,400 rpm and sonication for 10 min. The beads were resuspended to 0.004% (wt/vol) in hypertonic solution containing OVA before shocking. After osmotic shocking of the cells, free beads were removed by three washes in PBS.
OT-I cells from spleen and lymph nodes were washed twice in PBS containing 0.1% BSA. To label cells with the intracellular fluorescent dye carboxyfluorescein diacetate succinimidyl ester (CFSE; Molecular Probes) the cells were resuspended at 5 x 107 cells/ml in PBS/0.1% BSA with 10 µM CFSE for 10 min at 37°C. Cells were washed twice with cold RPMI 1640/10% FCS (RP10) followed by two washes in PBS. 106 CD8+V2+CFSE+ OT-I cells in 200 µl of PBS were injected into the tail vein.
14 h after injection with irradiated OVA-loaded β2m–/– cells, spleens of 5–35 mice were cut into grain size pieces and incubated in 1 ml per spleen of 1 mg/ml collagenase/dispase (Sigma-Aldrich) and 50 µg/ml DNase I (Boehringer) in PBS with continuous stirring at 37°C for 30 min or until digested. EDTA was added to a 10 mM final concentration, and the cell suspension was incubated for an additional 5 min at room temperature. RP10/10 mM EDTA/20 mM Hepes (RP10/HE) was added and the cells were pelleted. Red blood cells were lysed with ACK lysis buffer. Cells were washed once with RP10 and the cells were resuspended in 10 ml/5 spleens of RP10/HE. Undigested material was removed by filtration through a wire mesh screen and the cell suspension was loaded on 14.5% Accudenz (Accurate Chemical & Scientific Corporation) gradients in RP10/HE and centrifuged at 530 g for 20 min at room temperature 25. The low density fraction was recovered and washed once in RP10/HE and resuspended in RP10.
5 x 106 low density cells were incubated with 300 µl 2.4G2 supernatant (anti-Fc receptor) for 15 min on ice. Cells were then incubated with 200–250 µl of biotinylated antibody specific for CD11c, CD11b, CD8, or CD8β in PBS/0.1% BSA for 30 min at 4°C under slow rotation. Depletion of antibody-bound cells with streptavidin-coated magnetic beads (Dynal) was performed in PBS/0.1% BSA according to the manufacturer's instructions.
To detect OVA cross-priming, different DC preparations from injected mice were used as stimulators for naive OT-I cells in a [3H]thymidine incorporation assay. Indicated numbers of irradiated (2,250 rads) DCs were incubated with 105 OT-I RAG2–/– cells in flat-bottomed plates in 200 µl RP10. As a positive control, stimulator cells were coated with 1 µM OVA257–264 peptide for 1 h and washed three times. After 48 h, the plates were pulsed for 16 h with 1 µCi/well of [3H]thymidine and harvested.
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Cross-presentation to CD8+ T Cells In Vivo.
To study the MHC class I–restricted cross-presentation of cell-associated antigens, we injected B6 mice intravenously with β2m–/– cells that had been osmotically loaded with OVA. As expected, the injected cells are efficiently taken up and processed for MHC class I presentation by host APCs. This is demonstrated by the proliferative response of adoptively transferred, CFSE-labeled H2-Kb–restricted, OVA-specific TCR transgenic OT-I cells that serve as an indicator for efficient presentation in vivo. 3 d after priming, the transferred OT-I cells had divided up to seven times, as revealed by the sequential loss of CFSE intensity (Fig. 1 A). In contrast, OT-I cells did not proliferate in mice that did not receive OVA-loaded cells (Fig. 1 B).
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Only Lymphoid DCs Cross-present OVA Antigen to CD8+ T Cells.
To investigate further which cell population within the low density cell preparation was responsible for cross-presentation, we first evaluated which cell types were present. Flow cytometric analysis of the low density cells revealed four cell populations as defined by CD11c and CD11b staining (Fig. 3). A population of CD11c–CD11b– cells that consisted mainly of T and B cells made up 10–20% of the preparation. Besides these residual T and B cells, a population of CD11c– and CD11b– cells were detected that were autofluorescent in the FL-1, FL-2, and FL-3 channels, which could be misinterpreted as low level expression of CD11c and CD11b. The autofluorescent cells expressed MHC class I, heterogeneous levels of MHC class II, and low levels of the macrophage marker F4/80, but no CD4, CD8, or DEC205 (data not shown). This phenotype is consistent with recently described autofluorescent cells present in DC cell preparations that were identified as macrophages 28. Our low density cell preparation contained 30–40% myeloid and 10–30% lymphoid DCs, both expressing high levels of CD11c but different levels of CD11b (Fig. 3). Analysis of the myeloid and lymphoid DC subsets revealed high MHC class II expression by both subsets, high CD8 and DEC205 expression by the lymphoid DCs, and heterogenous CD4 and low DEC-205 expression by the myeloid DC subset, consistent with previously published studies 252628.
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antibodies. However, this depletion of the lymphoid DC subset was only 50% complete (22% predepletion to 13% postdepletion) with the preferential loss of the CD8high-expressing lymphoid DCs (data not shown). The specific depletion of CD8high lymphoid DCs resulted in significant loss of stimulatory activity (Fig. 4). Finally, depletion for CD8β+ cells did not lead to a significant change in numbers of the different subsets or in OVA cross-presenting activity. These results suggest that the lymphoid DC was the main cross-presenting APC. To confirm our findings, we isolated low density cells from mice injected previously with OVA-loaded β2m–/– cells and sorted myeloid and lymphoid DCs on the basis of their CD11b and CD11c expression. Sorting for myeloid and lymphoid DC populations resulted in 87 and 84% pure populations, respectively (Fig. 5 A). The sorted DC subsets were used as APCs for OT-I in an in vitro proliferation assay. Whereas sorted myeloid DCs lacked stimulatory capacity, sorted lymphoid DCs had stimulatory activity that was stronger than that of the starting DC preparation (Fig. 5 B). This result clearly demonstrates that only lymphoid DCs have the ability to cross-present antigen acquired in vivo from injected β2m–/– cells.
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1% of the lymphoid DC subset present OVA in vitro. |
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Further experiments showed that only the lymphoid DC subset cross-presents cell-associated antigens in MHC class I molecules in the spleen. The number of actual OVA-presenting cells is very low. We estimated that only 1% of lymphoid DCs present OVA to T cells. The lymphoid DC subset–restricted presentation was evident as early as 2 h after immunization, which strongly suggests that lymphoid DCs themselves take up the exogenous cell-associated antigen. Transfer of antigen between different DC subsets, as had been suggested, is therefore unlikely 414849. In support of the notion of direct uptake of antigen by lymphoid DCs, rat DCs containing apoptotic cell remnants have been found to migrate to the T cell areas of lymph nodes. These DCs were CD4– and may be the rat equivalent of the mouse lymphoid DCs 56. Our finding that only lymphoid DCs cross-present cell-associated antigens in the spleen does not preclude the presence of other types of APCs with cross-priming function in other tissues. APCs have been isolated from tumors and islets of Langerhans that could stimulate CD8+ T cells specific for tumor and islet antigens, respectively 575859. One of these studies defined the phenotype of the APCs as macrophage like 57.
Why do only lymphoid and not myeloid DCs cross-present cell-associated antigens to CD8+ T cells? In principle, it could be the result of differences in the uptake of cell debris, processing ability, or their T cell stimulatory capacity. We show that, in addition to lymphoid DCs, both autofluorescent macrophages and myeloid DCs contain cell-associated beads. This indicates that uptake of cell-associated antigen is not restricted to lymphoid DCs. This contrasts with the study by Fossum and Rolstad, in which allogeneic lymphocyte cell debris was found mainly in lymphoid DCs 60. However, differences in the in vivo model systems used may explain this discrepancy. Second, myeloid and lymphoid DCs do not seem to differ in their capacity to stimulate T cells, as both DC subsets have been shown to stimulate CD8+ T cells efficiently in vitro and in vivo 39. This leaves differences in antigen processing pathways between myeloid and lymphoid DCs as the most likely explanation. A selective transport of internalized antigens to the cytosol has been shown to occur in DCs and to be absent in macrophages 20. Both bone marrow–derived DCs and a splenic-derived DC line exhibited this ability, but ex vivo DCs were not evaluated. Our results suggest that this endosome to cytosol transport will be limited to lymphoid DCs.
Cross-presentation of cell-associated antigens to CD8+ T cells has been shown to result in either T cell activation or tolerance 1289106162. In both cases, bone marrow–derived cells are necessary 8910. Lymphoid DCs have been speculated to mediate peripheral tolerance, whereas myeloid DCs have been suggested to be essential for T cell stimulation 4963. Our studies do not specifically address the outcome of the DC–T cell interaction, as T cell proliferation is involved in both processes. However, our method of intravenous immunization with OVA-loaded cells has repeatedly been shown to lead to T cell activation and memory 106164. Therefore, we are convinced that we have isolated the APC required for CD8+ T cell cross-priming.
An attractive alternative explanation for the different outcomes of DC–T cell interaction is offered by several studies indicating that the activation state of the DCs is an important factor. DCs involved in cross-priming are activated via CD40–CD40L interaction provided by CD4+ T cells 646566. CD8+ T cell cross-priming does not occur in the absence of CD4+ T cells, illustrating the crucial role of CD4+ T cells in this process 10. Likewise, CD4+ T cells play an important role in preventing the induction of CD8+ T cell tolerance to self-antigens, as the addition of antigen-specific CD4+ T cells converts CD8+ T cell tolerance induction into CD8+ T cell activation 67. Furthermore, in several other tolerance induction systems, in vivo CD40 activation resulted in abrogation of tolerance and in T cell activation 68697071. Taken together, these studies strongly suggest that the activation state of the DCs is an important factor in determining the outcome of the DC–T cell interaction and that lymphoid DCs may be implicated in both activation and tolerization of antigen-specific CD8+ T cells.
Recent studies suggest different functions for lymphoid and myeloid DCs in the activation of CD4+ T cells, preferentially inducing Th1 and Th2 responses, respectively 404142. The capacity of lymphoid DCs to drive Th1 responses is explained by their production of IL-12 and IFN-
275272. Furthermore, the localization of the different DC and Th subsets appears to be similar. Th1 cells primarily reside in proximity to the lymphoid DCs in the central T cell zone of the PALS, whereas Th2 cells are found in the outer PALS near the B cell follicles and the marginal zone where myeloid DCs are located 73. Differential chemokine receptor expression patterns in both Th and DC subsets are essential in establishing this homing pattern 73747576. Our data add a new role for the lymphoid DCs as the main stimulator of CD8+ T cell responses specific for cell-associated antigens. This points to an interaction between lymphoid DCs, CD8+ T cells, and Th1 cells. It remains to be investigated whether CD8+ T cell cross-priming is specifically associated with and dependent on Th1 responses.
In summary, our data demonstrate that lymphoid DCs play a key role in cross-presentation of cell-associated antigens to CD8+ T cells in vivo. Because cross-presentation enables the activation of naive T cells specific for antigens that are not expressed by the APCs themselves, we envisage that lymphoid DCs will be essential for the induction of a large spectrum of CD8+ T cell responses.
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Acknowledgments |
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This work was supported by the Howard Hughes Medical Institute and by postdoctoral fellowships from the European Molecular Biology Organization (ALTF 115-1998) and from the Dutch Cancer Society to J.M.M. den Haan.
Submitted: 1 August 2000
Revised: 21 September 2000
Accepted: 31 October 2000
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