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The Journal of Immunology, 2003, 171: 4479-4483.
Copyright © 2003 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Dendritic Cell Actin Cytoskeletal Polarization during Immunological Synapse Formation Is Highly Antigen-Dependent 1

Monther M. Al-Alwan*, Robert S. Liwski*, S. M. Mansour Haeryfar*, William H. Baldridge{dagger}, David W. Hoskin*,{ddagger}, Geoffrey Rowden{ddagger},§ and Kenneth A. West2,*,{ddagger},§

Departments of * Microbiology and Immunology, {dagger} Anatomy and Neurobiology, {ddagger} Pathology, and § Medicine, Dalhousie University, Halifax, Nova Scotia, Canada


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Dendritic cells (DC) actively rearrange their actin cytoskeleton to participate in formation of the immunological synapse (IS). In this study, we evaluated the requirements for DC participation in the IS. DC rearrange their actin cytoskeleton toward naive CD4+ T cells only in the presence of specific MHC-peptide complexes. In contrast, naive CD4+ T cells polarized their cytoskeletal proteins in the absence of Ag. DC cytoskeletal rearrangement occurred at the same threshold of peptide-MHC complexes as that required for T cell activation. Furthermore, T cell activation was inhibited by specific blockade of DC cytoskeletal rearrangement. When TCR-MHC interaction was bypassed by using Con A-activated T cells, DC polarization was abrogated. In addition, directional ligation of MHC class II resulted in DC cytoskeletal polarization. Our findings suggest that a high Ag specificity is required for DC IS formation and that MHC class II signaling plays a central role in this process.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The engagement of TCR with peptide-MHC on the APC is facilitated by the formation of a specialized junction between the T cell and the APC referred to as the immunological synapse (IS) 3 (reviewed in Ref.1). Formation of the IS results in dynamic clustering of T cell surface receptors and signaling molecules into specialized domains (2) and is dependent on actin-myosin motors (3). These changes in the T cell actin cytoskeleton are likely of major functional importance because inhibition of T cell actin cytoskeletal rearrangement with cytochalasin D (CytD) prevents surface receptor clustering, T cell proliferation, and IL-2 production (4), although other models suggest that the cytoskeleton may play only an indirect role (5).

Dendritic cells (DC) are the most potent APC (6). We have recently shown that DC focally polarize their filamentous actin (F-actin) and fascin, a DC-specific actin-bundling protein, toward the interface with resting allogeneic CD4+ T cells (7, 8). In this study, we used a TCR transgenic system to demonstrate that the DC cytoskeletal reorganization during formation of the IS with naive CD4+ T cells was highly Ag-dependent. In contrast, participation of the naive CD4+ T cell cytoskeleton in the IS was Ag-independent. DC cytoskeletal rearrangement, which was induced via directional ligation of MHC class II, occurred at the same concentration of peptide-MHC complexes that was critical for T cell activation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Abs and reagents

The anti-fascin mAb was from DAKO (Carpinteria, CA). Anti-CD4 (GK1.5), PE-anti-CD44 (IM7.8.1), PE-anti-CD62 ligand (CD62L) (MEL-14), anti-CD11c (N418), anti-B7-2 (RMMP-2), anti-CD3{epsilon} (145-2C11), anti-CD25 (PC61.5.3), and FITC/PE-conjugated secondary Abs were from Cedarlane Laboratories (Hornby, Ontario, Canada). PE-anti-MHC class II (2G9) Ab was from BD PharMingen (San Diego, CA). Con A was from Sigma-Aldrich (St. Louis, MO). Alexa 488 goat anti-mouse IgG and Alexa Fluor 546 or 488 phalloidin were from Molecular Probes (Eugene, OR). CytD (Sigma-Aldrich), jasplakinolide (Jasp), and latrunculin A (LatA) (Molecular Probes) were dissolved in DMSO. The agonist (OVA323–339; ISQAVHAAHAEINEAGR) and control (OVA324–334; SQAVHAAHAEI) peptides were from Bethyl Laboratories (Montgomery, TX).

Cell culture and isolation

Mature mouse DC were prepared from BALB/c, C57BL/6 (Charles River Breeding Laboratories, Wilmington, MA) or MHC class II-deficient bone marrow (The Jackson Laboratory, Bar Harbor, ME) as previously described (7) using recombinant murine GM-CSF (Cedarlane Laboratories) and LPS (Sigma-Aldrich). The resulting DC were routinely >95% CD11c, MHC class II, and B7-2 positive by flow cytometry.

DO11.10 and OTII transgenic mice expressing IAd and I-Ab-restricted TCR specific for the chicken OVA323–339, respectively, were obtained from the National Institutes of Health (Bethesda, MD). Naive CD4+ T cells from spleen were negatively selected using a naive CD4 recovery column (R&D Systems, Minneapolis, MN) and were naive as assessed by CD62L+ and CD44low expression on FACS. Routinely, >82% of the resulting CD4+ T cells express the TCR transgene.

DC-T cell cluster analysis and T cell activation assay

DC were prepulsed for 2 h with varying concentrations of agonist or control peptide. In some experiments, DC were treated with graded doses of the actin polymerization inhibitors CytD, LatA, or Jasp for 1 h at 37°C and washed three times. DC were centrifuged with T cells (1:3) at 50 x g for 5 min then incubated at 37°C in a water bath for 30 min, resuspended, plated on poly-L-lysine-coated slides, fixed, stained, and examined under a Zeiss LSM510 confocal laser scanning microscope (Oberkochen, Germany). DC-T cell conjugates were divided into four quadrants and scored as polarized if the intensity of staining was greater in the quadrant adjacent to the T cell. At least 50 conjugates were evaluated blindly in each treatment group by three independent individuals. Binding assays were performed as described (7). For T cell activation, peptide-prepulsed DC were mixed with 105 naive transgenic CD4+ T cells (1:25) for 3 days. T cell proliferation was assessed by measuring thymidine incorporation in the last 18 h of incubation.

DC-bead cluster analysis

Carboxylated polystyrene beads (10 µm; Polysciences, Warrington, PA) were labeled with different secondary Abs for 2 h at 37°C. DC were incubated with anti-MHC class II (MK-D6), anti-MHC class I (34-5-8S), anti-B7-2 (RMMP-2), anti-LFA-1 (FD441.8) or no primary Abs for 45 min at 4°C. After extensive washing, DC prelabeled with the primary Ab were added to beads prelabeled with the appropriate secondary Ab. DC beads (2:1) were incubated in a 37°C water bath for 30 min, and plated on poly-L-lysine-coated slides. Slides were fixed, stained for F-actin, and analyzed for polarization as above.

IL-2 mRNA expression

DC were prepulsed with 300 nM agonist peptide before mixing with naive CD4+ T cells (1:25) as described above. IL-2 mRNA in cocultures was determined using semiquantitative RT-PCR. IL-2 cDNA was amplified for 29 cycles, which was determined previously to generate PCR product during the exponential phase of amplification.

Statistics

Statistical significance was assessed using a one-way ANOVA (GraphPad InStat, San Diego, CA). Wherever stated, NS denotes a p value of >0.05, while ** and *** indicate p values of <0.01 and <0.001, respectively.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
DC actin cytoskeletal rearrangement during IS formation is highly Ag-dependent

To determine the specificity of DC participation during formation of the IS, we evaluated the polarization of DC actin cytoskeletal proteins during DC-T cell interactions using the DO11.10 TCR transgenic model. In the presence of agonist peptide, DC-forming conjugates with naive CD4+ T cells demonstrated polarized expression of F-actin and the DC-specific actin bundling protein, fascin, toward the T cell interface (Fig. 1C). In contrast, there was no polarization of F-actin or fascin in DC bound to T cells in the absence of peptide or in the presence of similar doses of control peptide (Fig. 1, A and B). Similar results were seen with OTII transgenic T cells (data not shown). DC were able to polarize toward more than one T cell. The percentage of agonist peptide-pulsed DC that polarized their F-actin toward the interface with the T cells was 91% compared with 15 and 18% polarization in control DC and DC pulsed with control peptide, respectively (Fig. 2A). In these studies, DC-T cell binding increased significantly over time and reached a maximum by 30 min (Fig. 2B). Despite the low levels of T cell binding by DC at the earlier time points, the majority of DC polarized their F-actin and fascin as early as 5 min although there was also an increase over time (Fig. 2C). Interestingly, polarization of F-actin or talin, a cytoskeletal protein previously used to evaluate T cell cytoskeletal rearrangement, in naive CD4+ T cells occurred in the absence of agonist peptide (Fig. 2D) and in the absence of MHC class II (data not shown). This is in agreement with recent reports demonstrating that naive CD4+ T cells may form Ag-independent synapses with DC (9) and that talin can polarize in the absence of TCR signaling (10). Together, these data indicate that actin cytoskeletal rearrangement in DC leading to IS formation is highly Ag-dependent and specific.



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  		FIGURE 1. DC actin cytoskeletal rearrangement is highly Ag-dependent. DC-T cell conjugates were stained for F-actin and fascin and examined by confocal microscopy. In A–C, a–c represent the true color, the d and e represent the staining intensity (blue to red = low to high), and f shows the Nomarski image. A, No polarization of F-actin (a and d) or fascin (b and e) in DC-binding T cells in the absence of peptide. B, No polarization of F-actin (a and d) or fascin (b and e) in control peptide (300 nM)-pulsed DC-binding T cells. C, Polarization of both F-actin (a and d) and fascin (b and e) in agonist peptide (300 nM) pulsed-DC binding T cells. Polarization is representative of three independent experiments with >50 conjugates per experiment.

 


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  		FIGURE 2. Kinetics of DC polarization. A, Percentage polarization of F-actin and fascin in DC binding T cells expressed as mean polarization ± SD. B, DC pulsed with agonist peptide (300 nM) were labeled with CFMDA dye and mixed with T cells labeled with CM-Dil dye. Conjugates were counted using an inverted fluorescence microscope. The number of T cells bound to 100 DC at different time points is expressed as the mean ± SD. C, Percentage polarization of fascin in agonist peptide (300 nM)-pulsed DC binding T cells at different time points. D, Percentage polarization of F-actin or talin in T cells binding to DC. Polarization results are expressed as mean polarization ± SD of 50 conjugates and are representative of three independent experiments.

 
DC cytoskeletal polarization and T cell proliferation occur at the same threshold of MHC-peptide complexes

The concentration of peptide required for T cell activation and its relationship to DC actin cytoskeletal rearrangement were directly compared. DC were pulsed with various doses of peptide and one-half of the DC sample was used to determine T cell proliferation while the remainder was used to evaluate DC polarization. Polarization of DC fascin (Fig. 3A) and F-actin (data not shown) toward the T cell interface, as well as T cell proliferation (Fig. 3B), were peptide dose-dependent. Importantly, significant DC polarization and T cell proliferation were observed starting at the same agonist peptide concentration of 0.05 nM (Fig. 3, A and B). Furthermore, DC polarization and T cell activation were highly correlated (correlation coefficient of 0.98). This demonstrates that polarization of the DC cytoskeleton occurs at the same threshold of peptide-MHC complexes that results in T cell activation.



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  		FIGURE 3. DC cytoskeletal polarization occurs at the same peptide threshold as does T cell activation. A, Percentage polarization of fascin in DC binding T cells in the presence of different doses of peptide. The results are expressed as mean polarization ± SD of 50 clusters. B, Proliferation of T cells mixed with DC prepulsed with various doses of agonist peptide was assessed by measuring thymidine uptake. The results are expressed as mean dpm ± SD. C, Semiquantitative IL-2 RT-PCR: control (DMSO), CytD (20 µM), or Jasp (10 µM)-pretreated DC were incubated with T cells in the presence (300 nM) of agonist peptide, and IL-2 and GAPDH mRNA expression was determined from total RNA. D, T cell proliferation was assessed by measuring thymidine uptake. Control or LatA (5 µM)-pretreated, peptide-pulsed DC were mixed with T cells. The results are expressed as mean dpm ± SD. All results are representative of five independent experiments.

 
Actin cytoskeletal rearrangement in DC is critical for T cell activation

To evaluate the functional significance of DC participation in the IS, we determined the effects of inhibiting DC actin cytoskeletal rearrangement on IL-2 mRNA expression and T cell proliferation, as early and late markers of T cell activation, respectively. The earliest time point at which IL-2 mRNA was detected in T cells mixed with DC and peptide was 4 h (Fig. 3C). Pretreatment of DC with the actin cytoskeletal inhibitors, Jasp or CytD (11), abolished the expression of IL-2 mRNA (Fig. 3C). Only T cells produced IL-2 in our system as determined by intracellular IL-2 staining assessed by flow cytometry and T cell intracellular IL-2 production was also significantly decreased at 48 h by pretreatment of the DC with cytoskeletal inhibitors (data not shown). Furthermore, pretreatment of DC with LatA significantly reduced their ability to induce T cell proliferation at all agonist peptide doses (Fig. 3D). Similar results were obtained when DC were pretreated with CytD or Jasp (data not shown). There was no difference in cytoskeletal polarization in T cells interacting with Jasp or control-treated DC (data not shown). This indicates that the DC cytoskeleton is important for naive T cell activation at low as well as at high peptide doses. Altogether, our data suggest a direct relationship between DC cytoskeletal participation in the IS and T cell activation.

Polarization of the DC’s cytoskeleton is induced via MHC class II ligation

The fact that DC form the IS only in the presence of peptide suggests that DC involvement in this process may be triggered through MHC class II signaling. Alternatively, TCR signaling may activate other T cell surface molecules that trigger DC polarization by binding to their corresponding ligands. We bypassed MHC class II-peptide-TCR interactions by directly activating naive CD4+ T cells with Con A before clustering with control- or peptide-pulsed DC. Con A-activated T cells did not induce DC polarization in the absence of agonist peptide (Fig. 4, A and E). However, in the presence of agonist peptide, Con A-activated T cells were able to restore DC fascin polarization to nearly the control levels (Fig. 4, B and E). This indicates that MHC class II-peptide-TCR interactions are required for DC cytoskeletal rearrangement.



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  		FIGURE 4. DC actin cytoskeletal reorganization is triggered via directional MHC class II ligation. T cells were activated with Con A (2.5 µg/ml) before mixing with control (A)- or peptide (B)-pulsed DC and evaluated for DC cytoskeletal polarization. DC labeled with anti-MHC class II (D) or anti-LFA-1 (E) Abs were mixed with beads coated with secondary Abs, stained for F-actin, and evaluated by confocal microscopy. In A–D, a–c represent the true color, the staining intensity (blue to red = low to high), and the Nomarski image, respectively. E, Percentage polarization of fascin in DC binding Con A-activated T cells in the presence or absence of peptide. F, Percentage polarization of F-actin in DC labeled with different primary Abs and mixed with secondary Ab-coated beads. The results in E and F are expressed as mean percentage polarization ± SD of 50 conjugates and are representative of three independent experiments.

 
To directly explore the role of MHC class II molecules in DC participation in the IS, we made surrogate T cells using polystyrene beads to directionally cross-link specific proteins on the surface of the DC. Our data demonstrated that >50% of DC polarize their actin cytoskeleton following directional MHC class II cross-linking (Fig. 4, C and F). In contrast, <20% F-actin polarization was observed in DC when MHC class I, B7-2, or LFA-1 were cross-linked (Fig. 4, D and F). This demonstrates an important role for MHC class II signaling in Ag-dependent DC participation in the IS.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study demonstrates that DC reorganize their actin cytoskeleton during formation of the IS in an Ag-dependent manner, while naive CD4+ T cell participation in this process does not require Ag. In addition, DC actin cytoskeletal involvement in the IS, which is mediated through MHC class II ligation, occurs at the same peptide-MHC threshold required for T cell activation. This indicates that cytoskeletal rearrangement by DC binding to naive CD4+ T cells in an Ag-specific fashion may define the threshold for activation of naive T cells.

Our results suggest different roles for DC and naive T cell cytoskeletal rearrangement in the process of synapse formation. Consistent with our findings, a recent study has demonstrated that naive CD4+ T cells can form synapses with DC in an Ag-independent manner (9). These "presynapses" might allow naive T cells to sample Ag on DC. Other work in vivo suggests that full TCR polarization requires the presence of self MHC class II (12). Upon recognition of the appropriate Ag a mature synapse is then established that requires the participation of the DC cytoskeleton.

Because DC actin cytoskeletal rearrangement only occurs in the presence of the appropriate Ag, it is probably not critical for Ag sampling. Rather, DC actin cytoskeletal polarization may influence T cell activation by enhancing DC-T cell interactions. We previously demonstrated a crucial role for the DC cytoskeleton in stabilizing DC-T cell binding (7). The DC cytoskeleton may influence this process through activation of integrins and changes in the T cell-DC contact area that occur in the presence of Ag (13). This could explain the prolonged synapses that are seen in vivo (14). Rearrangement of the DC actin cytoskeleton may also participate in the directional secretion of cytokines toward Ag-specific T cells (15). A more recent study also demonstrated the transport of MHC class II molecules in the DC toward the area of contact with T cells in an Ag-dependent manner (16). However, MHC class II may also cluster passively in response to changes occurring in the cytoskeleton of activated T cells (17).

Although DC bind multiple naive CD4+ T cells in an Ag-independent manner, the high Ag specificity required for DC participation in the IS is likely to ensure that only Ag-specific T cells receive activation signals. By creating a microenvironment for Ag-specific T cell activation, the DC could prevent inappropriate stimulation of neighboring Ag-nonspecific T cells. The high Ag specificity required for DC participation in the synapse may synergize with the specificity of the T cell signaling process to increase the overall specificity of the T cell activation process. Further studies will be required to determine whether other APC participate in the IS in a similar manner.

Our bead data also demonstrate an important role for MHC class II signaling in initiating Ag-dependent DC cytoskeletal rearrangement. Interestingly, ligation of MHC class II molecules has also been shown to enhance cell-cell adhesion (18) and treatment of DC with anti-MHC class II Abs induces homotypic aggregation (19). Similarly, we observed homotypic clustering of DC that were treated with anti-MHC class II Ab and were not bound by beads (data not shown). The fact that we observed no polarization of DC binding activated T cells in the absence of Ag implicates MHC class II as the primary molecule that initiates DC participation in the IS. However, we see more DC cytoskeletal polarization when T cells bind DC compared with directional MHC class II cross-linking using beads. This suggests that the binding of other receptor-ligand pairs between DC and T cells further contributes to enhance DC polarization.


   Acknowledgments
 
We thank Julie Bunker for technical assistance.


   Footnotes
 
1 This work was supported by grants (to K.A.W. and G.R.) from the Kidney Foundation of Canada, Nova Scotia Health Research Foundation, Canadian Institutes for Health Research, and National Cancer Institute of Canada. M.M.A.-A. was supported by a studentship from the Government of Saudi Arabia. Back

2 Address correspondence and reprint requests to Dr. Kenneth A. West, Department of Medicine, Dalhousie University, Suite 5087, Dickson Building, 5820 University Avenue, Halifax, Nova Scotia, B3H 2Y9 Canada. E-mail address: kawest{at}dal.ca Back

3 Abbreviations used in this paper: IS, immunological synapse; CytD, cytochalasin D; DC, dendritic cell; F-actin, filamentous actin; CD62L, CD62 ligand; Jasp, jasplakinolide; LatA, latrunculin A. Back

Received for publication February 3, 2003. Accepted for publication September 12, 2003.


   References
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 Introduction
 Materials and Methods
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 Discussion
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F. Benvenuti, S. Hugues, M. Walmsley, S. Ruf, L. Fetler, M. Popoff, V. L. J. Tybulewicz, and S. Amigorena
Requirement of Rac1 and Rac2 Expression by Mature Dendritic Cells for T Cell Priming
Science, August 20, 2004; 305(5687): 1150 - 1153.
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N. Setterblad, S. Becart, D. Charron, and N. Mooney
B Cell Lipid Rafts Regulate Both Peptide-Dependent and Peptide-Independent APC-T Cell Interaction
J. Immunol., August 1, 2004; 173(3): 1876 - 1886.
[Abstract] [Full Text] [PDF]

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