CD1-dependent dendritic cell instruction

The importance of T cell−derived signals in the induction of fully competent dendritic cells (DCs) is widely accepted¹. However, few T cells have the capacity for cognate interaction with immature DCs at the critical early stages of an immune response. Existing evidence counters the hypothesis that naïve T helper cells themselves provide these signals^{2, 3, 4}. Two fundamental problems contribute to the inadequacy of naïve T cells in activating DCs: scarcity and timing. During initiation of the immune response, rare antigen-reactive naïve T cells with limited effector functions are poorly suited to assist in DC maturation. In vitro, activation of immature DCs leads to a developmental stage lasting only 12 h; during this stage interferon- (IFN-) can program these cells to produce interleukin 12 (IL-12)⁵. After this checkpoint, DCs lose the capacity to make IL-12 upon CD40 ligation as a result of "dendritic cell exhaustion"⁶. In contrast to rare foreign antigen−specific precursors, foreign antigen−independent T cells recognizing nonpolymorphic molecules expressed selectively on professional antigen-presenting cells are attractive candidates to supply the requisite early T cell signals involved in DC maturation. CD1a, CD1b and CD1c are highly restricted in their expression to professional antigen-presenting cells and are displayed at high amounts on immature DCs, whereas CD1d is expressed more broadly⁷. Thus, self-reactive CD1-restricted T lymphocytes might be capable of providing a timely source of T cell help for DC maturation.

Table 1. Self-reactive CD1-restricted and nonreactive control T cell clones. Full Table

Using our panel of CD1a, CD1b and CD1c self-reactive T cell clones, a panel of T cell receptor (TCR)−invariant CD1d-restricted natural killer T (NKT) cell clones^{14, 15} and a panel of control T cell clones that lacked reactivity to immature myeloid DCs, we first analyzed the transition from immature to mature DCs after culture of immature monocyte−derived DCs with graded numbers of T cells. A ratio as low as one CD1 self-reactive T cell clone in coculture with eight DCs increased CD86 expression by a factor of two to seven over controls, indicating phenotypic changes associated with DC maturation (Fig. 1a). When the ratio of T cells to DCs was raised to 1:2, the clones tested induced an increase in CD86 surface expression by as much as a factor of 12. The Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) induced the expected shift from a CD83^-CD86^- population to a CD83⁺CD86⁺ population, indicative of DC maturation (Fig. 1b). Similarly, the CD1 self-reactive T cell clone Ye2.3 and the CD1d-restricted T cell clones BM2a.3 and CAD1.1 led to a doubling of CD83 expression and an increase in CD86 expression by a factor of 15 to 30 (Fig. 1b). In conjunction with the changes in maturation markers, the redistribution of MHC class II (major histocompatibility complex) molecules from lysosomal-associated membrane protein-1 (LAMP-1)−bearing intracellular vesicles to the plasma membrane¹⁶ further illustrated that maturation induced by these T cell clones quantitatively and qualitatively resembled that induced by LPS (Fig. 1c). Similarly, the ability of DCs that had been cultured with CD1-reactive T cells to induce the proliferation of naïve alloreactive T cells was up-regulated, whereas their pinocytic activity, as assessed by fluorescein isothiocyanate (FITC)−dextran uptake, was diminished by 60−80% (data not shown). The DC maturation induced by the clones Ye2.14 and Ye2.3 was dependent upon the recognition of DC CD1, as CD1b or CD1c isoform−specific monoclonal antibodies (mAbs) blocked 60−90% of the CD86 up-regulation, respectively (Fig. 1d). Thus, CD1 self-reactive T cells efficiently induce expression of the maturation markers CD83 and CD86, characteristic changes in MHC class II localization and alterations in pinocytosis that are hallmarks of DC maturation. These T cell−induced DC maturation changes appear to be similar to those induced by the microbial product LPS.

Figure 1. CD1-dependent DC maturation. (a) Immature DCs were cultured with increasing ratios of CD1-reactive (filled squares, Mt1.50-CD1a; filled triangles, Ec2.55-CD1b; filled inverted triangles, Ye2.3-CD1c; filled circles, DN2.B9-CD1d) or control T cell clones (open circles, Mt2.6; open squares, P2.10) for 3 days and CD86 expression—mean fluorescence intensity (MFI)—was determined by flow cytometry (open triangle, DCs and medium; open inverted triangle, DCs and TNF- (10 ng/ml)). (b) Immature DCs and either medium alone, LPS (10 ng/ml) or the indicated clones were cultured for 36 h and analyzed by two-color flow cytometry with FITC-CD83 and PE-CD86 antibodies. BM2a.3 and CAD1.1 were derived by flow cytometric sorting of GalCer-loaded CD1d-tetramer+ bone marrow or cord blood mononuclear cells, respectively15. Data are representative of at least six independent experiments. (c) Cells from the cultures analyzed in b were removed at 36 h, fixed after cytospin preparation and analyzed by confocal microscopy after FITC−anti−MHC class II (green) or Texas red−anti−LAMP-1 (red) staining45. Merged data were acquired with the Leica TCS-NT laser scanning confocal microscope, and confocal images are representative of three independent experiments. (d) mAbs (40 g/ml) specific for CD1b (BCD1b3.1) or CD1c (F1021A3.1) were included in cocultures of the indicated CD1 self-reactive clones and immature DCs and analyzed as in a after a 60-h incubation. The ratio of T cells to DCs was 1:6. TNF- (10 ng/ml) served as a positive control. Results are representative of at least three independent experiments. Full Figure and legend (63K)

T cell products—including CD40 ligand (CD40L)^{17, 18}, receptor activator of NF-B ligand (RANKL)¹⁹, Fas ligand²⁰, tumor necrosis factor- (TNF-)¹⁷ and IFN-²—can contribute to DC maturation. We assessed the role played by each of these products and found that, for the group 1 CD1 self-reactive T cells, >50% inhibition of maturation was consistently observed only with TNF- blockade (Fig. 2a). In contrast, although CD1d-restricted T cell−induced maturation was similarly inhibited by blockade of TNF-, inhibition of RANKL, CD40L and IFN- also blocked CD86 up-regulation by 10−30% (Fig. 2b). This suggested that multiple T cell products could contribute to DC phenotypic maturation for the CD1d-restricted subset. CD40L is expressed by the CD1d-restricted subset of human T cells upon activation²¹. When we analyzed T cells in culture with DCs, we found increased expression of CD40L only on the CD1d-restricted subset (data not shown). To identify the source of cytokines in the cultures, we performed intracellular cytokine staining and examined expression of both TNF- and IFN- in the lymphocyte and DC populations. In each culture the T cells appeared to be the dominant source of TNF-, although there was weak expression by DCs in several cultures (Fig. 2c). We detected IFN- only in T cells (Fig. 2d). All the clones in our panel were capable of secreting IFN- but, unlike the CD1d-restricted human clones¹⁴, the group 1 CD1-restricted population produced no detectable IL-4 (unpublished data).

Figure 2. Inhibition of T cell−induced CD86 expression. (a) CD1c- or (b) CD1d-restricted clones were cultured at a ratio of 1 T cell to 5 DCs in the presence of the indicated blocking reagent at 10 g/ml or medium. After 36 h in culture, CD86 expression was assessed by flow cytometry. Each figure is representative of three independent experiments. OPG, osteoprotegerin. (c) TNF- or (d) IFN- were assessed by two-color intracellular cytokine staining of 24 h cocultures of the indicated T cell clones and DCs. Lymphocyte and DC gates were set on the basis of forward- and side-scatter properties. Results indicate the percentage of positively stained cells calculated after the subtraction of isotype control staining, which averaged <1%. Similar results were obtained after 48 h of coculture. Full Figure and legend (21K)

Figure 3. Differential cytokine production by DCs in the presence of LPS- and CD1-reactive T cells. (a) IL-12p70 and (b) IL-10 were measured in cultures in the presence (filled squares) or absence (open squares) of the indicated self-reactive T cell clones and graded concentrations of LPS. The ratio of T cells to DCs was 1:4. Supernatants from duplicate wells were analyzed by ELISA after 60 h. Mean s.d. data are shown and results are representative of at least six independent experiments with 12 distinct clones. (c) (Left panels) Each CD1-restricted (filled squares, group 1; filled triangles, group 2) or control (filled circles) T cell clone in our panel was incubated with immature DCs at a ratio of 1 T cell to 5 DCs in the presence of 10 ng/ml of LPS. Supernatants from triplicate cultures were analyzed by ELISA; the horizontal bars represent mean data. (Right panels) Production of IL-12 and IL-10 in the absence of T cells or LPS. n.d., not detectable. Mean s.d. (not visible) data are shown and results are representative of at least three independent experiments. Full Figure and legend (30K)

Next, we asked whether DCs matured in the presence of these different stimuli would differentially polarize naïve CD4⁺ T cells. Autologous naïve CD4⁺ T cells were stimulated with low-dose superantigen-pulsed myeloid DCs that had been matured in the presence of a CD1c or CD1d self-reactive T cell in the presence or absence of LPS. The capacity to promote T_H1 cell development, as measured by IFN- production, was limited to those DCs matured in the presence of the group 1 CD1-restricted T cell clone and LPS (Fig. 4b). Immature DCs or those DCs matured under the influence of LPS alone or with the CD1d-restricted clone, although not capable of inducing T_H1 polarization, were capable of activating naïve T cells because their proliferation was readily induced independently of IFN- production (Fig. 4a). IL-4 production was negligible in these cultures (data not shown), which indicated that in the absence of appropriate combined T cell and microbial signals, nonpolarized T_H cells result under the conditions of our assay. These findings were consistent with other data that have demonstrated a close correlation between the capacity of DCs to generate IL-12p70 and subsequent naïve CD4⁺ lymphocyte T_H1 polarization⁶.

Figure 4. T cell polarization by DCs. (a) Autologous naïve CD4+ T cells were stimulated by superantigen-pulsed DCs after the DCs had been cultured in the absence or presence of a CD1c (Ye2.3) or CD1d (DN2.B9) self-reactive T cell clones with or without LPS (10 ng/ml). The ratio of self-reactive T cell clones to DCs was 4:12. After pulsing with the superantigen TSST-1 (10 pg/ml), DCs were irradiated (5000 rad) and cultured in triplicate for 10 days with 1 104 naïve T cells before proliferation was measured by [3H]thymidine incorporation. Mean s.d. data are shown. (b) Supernatants from the cultures in a were removed on day 9, and IFN- was analyzed by ELISA. Data are plotted according to the ratio of self-reactive T cells to DCs in the maturation culture. DCs were matured in the presence of the CD1c-restricted T cell clone (Ye2.3) and LPS (filled circles). Mean s.d. data for immature DCs (open triangles), LPS-matured DCs (filled squares), Ye2.3-matured DCs without LPS (open circles) and DN2.B9-matured DCs with (filled squares) and without (open squares) LPS are shown. Full Figure and legend (16K)

The dichotomous influence of the CD1a-, CD1b- and CD1c- versus CD1d-restricted T cell subsets on DC cytokine production suggested that important differences existed in the T cell factors produced. For the CD1c-reactive T cell clone, IFN- and CD1c mAbs blocked the capacity of the Ye2.3 clone to induce IL-12p70 by 75% and 90%, respectively (Fig. 5). Antibody or soluble receptor blockade of FasL, CD40L or TNF- showed <25% inhibition of IL-12 secretion, and there was no effect of RANKL inhibition by osteoprotegerin. These data demonstrated that IFN- is important in promoting the T_H1-polarizing capacity of myeloid DCs by group 1 CD1-reactive T cell clones.

Figure 5. Factors that regulate IL-12 production by DCs. (a) The CD1c-restricted T cell clone Ye2.3 was cultured with immature DCs at a ratio of 1:5; LPS (10 ng/ml) and the indicated blocking reagents (10 g/ml) were also added. IL-12p70 was measured in supernatants from triplicate cultures after 36 h. The concentration of IL-12p70 in the absence of blocking reagents was 2.4 ng/ml per 106 DCs. (b) IL-12p70 production by DCs was determined in the presence of mAbs to IFN- (filled circles) and CD1c (filled squares) in cocultures with Ye2.3 and LPS (10 ng/ml). Isotype-matched anti-CD1d (open squares) and medium alone (open circles) controls are also shown. Data are representative of three independent experiments done with two distinct clones. Full Figure and legend (9K)

The absence of IL-12 production by the CD1d-restricted T cells contrasts with data from studies in the murine system linking NKT cell activation with IL-12 production²⁴. In addition, it was unexpected in light of the profound effect CD1d-restricted human T cell clones had on other features of DC maturation, such as CD83 and CD86 expression and MHC class II surface redistribution (Fig. 1). To investigate this further, we used the NKT cell agonist -galactosylceramide (GalCer) in culture with immature DCs and measured IL-12 production. Under conditions that included this potent lipid agonist, IL-12 was generated and was dependent on CD40L expression (Fig. 6). This was true for all CD1d-restricted T cell clones tested (data not shown). Neutralization of IFN- in these cocultures did not affect IL-12 production, in contrast to the inhibition seen when done in the presence of cocultures containing LPS and group 1 CD1-restricted self-reactive clones.

Figure 6. Differential mechanisms for IL-12p70 production for CD1 self-reactive cells. The indicated T cell clones were cocultured with immature DCs at a ratio of 1:5 in the presence or absence of GalCer (40 ng/ml) and LPS (10 ng/ml) and mAbs at 10 g/ml. Supernatants from triplicate wells were collected at 24 h and IL-12p70 was measured by ELISA. Mean s.d. data are shown; results are representative of at least three independent experiments done with five distinct clones. Full Figure and legend (7K)

	Top

We propose that the CD1-restricted subset of self-reactive T cells represents a source of the requisite T cell−derived signals that are involved in shaping the adaptive immune response to infection, by virtue of their TCRs' distinct capacities to recognize maturing myeloid DCs at an early stage of the systemic immune response. CD1a-, CD1b-, CD1c- and CD1d-restricted T cell clones were all able to induce phenotypic DC maturation and to stimulate bioactive IL-12 production. Beyond their differences in antigen molecule recognition, CD1a-, CD1b- and CD1c-reactive T cell clones required additional activation by a microbial product such as LPS, but CD1d-reactive T cell clones required a potent CD1-presented lipid antigen to elicit IL-12. Whereas IFN- was required to complement LPS for T cells responding to self-CD1a, self-CD1b and self-CD1c, CD40L was required to generate IL-12 from DCs responding to CD1d and its corresponding T cell agonist GalCer.

Although in our studies the requirements for DC instruction by CD1-restricted T cells differed on the basis of CD1 isoform specificity, isoform specificity itself is unlikely to dictate these requirements. Rather, the strength of the T cell−CD1 interaction and the complement of secreted and cell surface molecules expressed by the self-reactive T cell are likely the critical determinants of DC instruction. For example, only a more potent T cell signal (GalCer) for the CD1d-restricted subset enabled DCs to produce IL-12. In addition, CD1d-restricted T cells with a T_H1 bias are present in human liver²⁵, and group 1 self-reactive CD1-restricted cells from lupus patients can express IL-4 and CD40L²⁶. Our data suggested that the interaction of IFN-−producing CD1 self-reactive cells in the context of a microbial stimulus will result in effective T_H1-biased adaptive immunity. In the absence of IFN- or a potent CD1-presented lipid antigen, one might encounter a tolerizing effect of CD1-restricted T cells arising from their propensity to generate nonpolarizing DCs.

Previous studies have emphasized the importance of CD40L expression on CD4⁺ T cells in the provision of T cell help for DC maturation^{17, 18}. Our study underscores the potential of the CD8⁺ T cell pool to participate in conditioning DCs via their abundant IFN- production. Several other reports have described alternative sources for lymphocyte factors capable of providing early help for DC instruction. For example, CD45RA⁺CD8⁺ T cells can rapidly generate TNF- and IFN- to mediate DC instruction²⁷, but in the naïve host, only a minute pool of pathogen-specific cells is present. Similarly, NK cells can provide help to maturing DCs, yet previous activation or large numbers of NK cells are required^{28, 29, 30}.

The self-reactive CD1-restricted subset of T cells appears to be the most potent lymphocyte population thus far identified capable of activating immature monocyte−derived DCs. Although the frequency of group 1 CD1-restricted T cells is unknown, the mean percentage of CD1d-restricted T cells is 0.2% in normal human blood¹⁵ and may be considerably larger in some tissues³¹. In our analysis, 500 clones screened from seven separate lines yielded 14 that were self-reactive to CD1a, CD1b or CD1c; this suggested that as many as two or three such precursors could be present per 100 circulating T lymphocytes in normal individuals. Semi-invariant TCR chain CD1d-restricted T cells in both mice and humans also appear to function as effector lymphocytes. The access of effector T cells to peripheral tissues^{32, 33} raises the possibility that self-reactive CD1-restricted T cells encounter DCs at the site of an inflammatory insult. Human NKT cells express chemokine receptors such as CCR2 and CCR5, which are characteristic of effector memory cells^{34, 35}. The respective chemokine ligands for these receptors, MCP-1 (monocyte chemoattractant protein 1; also called CCL2) and MIP-1 (macrophage inflammatory protein 1; CCL4), are up-regulated rapidly by myeloid DCs in the context of microbial stimuli^{36, 37}. Thus, the rapid release of such effector T cell chemoattractants reinforces the concept that T cells recruited early in infection are likely to participate in DC maturation.

	Top

Immature monocyte−derived DCs and lymphocytes were prepared from leukapheresis mononuclear cells obtained in accordance with institutional guidelines. Mononuclear cells isolated by Ficoll-Hypaque density centrifugation (Amersham Biotech, Piscataway, NJ) were enriched for monocytes by plastic-adherence and immature monocyte−derived DCs were derived by culture in 300 U/ml of granulocyte-macrophage colony-stimulating factor (GM-CSF, Sargramostim, Immunex, Seattle, WA) and 200 U/ml of IL-4 (PeproTech, Rocky Hill, NJ) in complete RPMI medium for 2−4 days as described⁴¹. For the derivation and characterization of T cell clones, CD4⁺ T cells from nonadherent mononuclear cells were depleted with antibody-conjugated magnetic beads and a VarioMACS apparatus according to the manufacturer's specifications (Miltenyi Biotec, Auburn, CA). Cell lines were established in 24-well plates with 10⁶ CD4-depleted T cells and 10⁶ irradiated (5000 rad, ¹³⁷Cs source) autologous monocyte-derived DCs and lipid-enriched bacterial preparations (1−5 g/ml). Established lines were restimulated under the same conditions at 10−14 day intervals before cloning. T cell lines were cloned by limiting dilution as described⁴². CD1d-restricted T cells were previously characterized¹⁴ or cloned by flow cytometric sorting of GalCer-loaded CD1d tetramer⁺ cells as described¹⁵.

Cultures of DCs with T cells were done at a DC density of 10⁶ cells per ml in complete RPMI medium unless otherwise noted. In some experiments GM-CSF and IL-4 concentrations were maintained in the cocultures, although those cytokines were not critical to the results described. T cells clones were added at a ratio of 1 T cell to 5 DCs unless otherwise stated. Escherichia coli LPS (serotype O55:B5, L2880, Sigma-Aldrich Co., St. Louis, MO) or TNF- (10 ng/ml, Peprotech) were added at the initiation of coculture where indicated. All cytokine ELISAs were done in triplicate with matched antibody pairs according to the manufacturer's instructions (Pierce Endogen, Rockford, IL). For analysis of intracellular cytokines, the ratio of T cell clones to DCs was 1:3 and staining was done after 24 h of coculture.

Polarization by instructed DCs was done with autologous CD4⁺CD45RA⁺ cells isolated by negative selection with a commercial kit according to the manufacturer's instructions (R&D Systems, Minneapolis, MN). DCs were pulsed with toxic shock syndrome toxin-1 (TSST-1, 10 pg/ml, Toxin Technology, Sarasota, FL) after coculture in the absence or presence of CD1c (Ye2.3) or CD1d (DN2.B9) self-reactive T cell clones and with or without LPS (10 ng/ml). The ratio of self-reactive T cell clones to DCs varied from 1:12 to 4:12. After pulsing with superantigen, DCs were irradiated (5000 rad) and 1 10⁵ DCs were cultured in triplicate for 10 days with 1 10⁴ naïve T cells before proliferation was measured. Proliferation of autologous naïve CD4⁺ T cells was measured by overnight [³H]thymidine (PerkinElmer, Wellesley, MA) incorporation as described⁴². IFN- in the supernatants of these cultures was measured by ELISA 1 day before determination of proliferation, as described above.

Antibodies and soluble inhibitors for blocking studies included BCD1b3.1 (CD1b)⁴³, F10/21A3.1 (CD1c)⁴², CD1d42.1 (CD1d)¹⁴, anti−IFN- (R&D Systems), anti−TNF- (Pierce Endogen), Fas-Fc (Becton Dickinson, Franklin Lakes, NJ), Osteoprotegerin (Peprotech) and anti-CD40L (Serotec, Raleigh, NC). Antibodies for flow cytometry included OKT4 (American Type Culture Collection, Manasses, VA), phycoerythrin (PE)−CD8, FITC-CD83, PE-CD86, PE−TNF- and isotype-matched controls (Becton Dickinson). FITC-anti−IFN- was from Caltag (Burlingame, CA). Antibodies for confocal microscopy included L243 (American Type Culture Collection) for HLA-DR, rabbit polyclonal antisera to LAMP-1⁴⁴, FITC-conjugated donkey F(ab')₂ antibody to mouse IgG and Texas red−conjugated donkey F(ab')₂ antibody to rabbit IgG (Jackson ImmunoResearch Laboratories, West Grove, PA).

Flow cytometry data was acquired on a FACSort flow cytometer (Becton Dickinson). Cocultures of various clones and immature DCs were performed as indicated and analyzed by two-color flow cytometry with FITC-CD83 and PE-CD86 antibodies, FITC−IFN- and PE−TNF- or by confocal microscopy with anti-MHC class II (FITC) or LAMP-1 (Texas red) staining of cytospin preparations as described⁴⁵. Intracellular cytokine staining was done with a Cytofix-Cytoperm kit after a 4-h incubation with Golgi Stop according to the manufacturer's instructions (Becton Dickinson). Flow cytometry data was analyzed with WinMDI software (Joseph Trotter, The Scripps Research Institute, La Jolla, CA). Confocal data was acquired with a Leica TCS-NT microscope fitted with krypton and argon lasers.

	Top

1. Lanzavecchia, A. & Sallusto, F. Regulation of T cell immunity by dendritic cells. Cell 106, 263–266 (2001). | Article | PubMed | ISI | ChemPort |
2. Hilkens, C.M., Kalinski, P., de Boer, M. & Kapsenberg, M.L. Human dendritic cells require exogenous interleukin-12-inducing factors to direct the development of naive T-helper cells toward the Th1 phenotype. Blood 90, 1920–1926 (1997). | PubMed | ISI | ChemPort |
3. Schulz, O. et al. CD40 triggering of heterodimeric IL-12p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity 13, 453–462 (2000). | Article | PubMed | ISI | ChemPort |
4. Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–779 (2001). | Article | PubMed | ISI | ChemPort |
5. Kalinski, P., Schuitemaker, J.H., Hilkens, C.M., Wierenga, E.A. & Kapsenberg, M.L. Final maturation of dendritic cells is associated with impaired responsiveness to IFN- and to bacterial IL-12 inducers: decreased ability of mature dendritic cells to produce IL-12 during the interaction with Th cells. J. Immunol. 162, 3231–3236 (1999). | PubMed | ISI | ChemPort |
6. Langenkamp, A., Messi, M., Lanzavecchia, A. & Sallusto, F. Kinetics of dendritic cell activation: impact on priming of T_H1, T_H2 and nonpolarized T cells. Nature Immunol. 1, 311–316 (2000). | Article | PubMed | ISI | ChemPort |
7. Porcelli, S.A. & Modlin, R.L. The CD1 system: antigen-presenting molecules for T cell recognition of lipids and glycolipids. Annu. Rev. Immunol. 17, 297–329 (1999). | Article | PubMed | ISI | ChemPort |
8. Benlagha, K. & Bendelac, A. CD1d-restricted mouse V14 and human V24 T cells: lymphocytes of innate immunity. Semin. Immunol. 12, 537–542 (2000). | Article | PubMed | ISI | ChemPort |
9. Beckman, E.M. et al. Recognition of a lipid antigen by CD1-restricted ⁺ T cells. Nature 372, 691–694 (1994). | Article | PubMed | ChemPort |
10. Sieling, P.A. et al. CD1-restricted T cell recognition of microbial lipoglycan antigens. Science 269, 227–230 (1995). | PubMed | ISI | ChemPort |
11. Moody, D.B. et al. Structural requirements for glycolipid antigen recognition by CD1b-restricted T cells. Science 278, 283–286 (1997). | Article | PubMed | ISI | ChemPort |
12. Shamshiev, A. et al. Self glycolipids as T-cell autoantigens. Eur. J. Immunol. 29, 1667–1675 (1999). | Article | PubMed | ISI | ChemPort |
13. Shamshiev, A. et al. Presentation of the same glycolipid by different CD1 molecules. J. Exp. Med. 195, 1013–1021 (2002). | Article | PubMed | ISI | ChemPort |
14. Exley, M., Garcia, J., Balk, S.P. & Porcelli, S. Requirements for CD1d recognition by human invariant V24⁺ CD4^-CD8^- T cells. J. Exp. Med. 186, 109–120 (1997). | Article | PubMed | ISI | ChemPort |
15. Gumperz, J.E., Miyake, S., Yamamura, T. & Brenner, M.B. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J. Exp. Med. 195, 625–636 (2002). | Article | PubMed | ISI | ChemPort |
16. Pierre, P. et al. Developmental regulation of MHC class II transport in mouse dendritic cells. Nature 388, 787–792 (1997). | Article | PubMed | ISI | ChemPort |
17. Sallusto, F. & Lanzavecchia, A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J. Exp. Med. 179, 1109–1118 (1994). | Article | PubMed | ISI | ChemPort |
18. Caux, C. et al. Activation of human dendritic cells through CD40 cross-linking. J. Exp. Med. 180, 1263–1272 (1994). | Article | PubMed | ISI | ChemPort |
19. Anderson, D.M. et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175–179 (1997). | Article | PubMed | ISI | ChemPort |
20. Rescigno, M. et al. Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1, and the production of interferon in the absence of IL-12 during DC-T cell cognate interaction: a new role for Fas ligand in inflammatory responses. J. Exp. Med. 192, 1661–1668 (2000). | Article | PubMed | ISI | ChemPort |
21. Nieda, M. et al. Dendritic cells rapidly undergo apoptosis in vitro following culture with activated CD4⁺ V24 natural killer T cells expressing CD40L. Immunology 102, 137–145 (2001). | Article | PubMed | ISI | ChemPort |
22. Vieira, P.L., de Jong, E.C., Wierenga, E.A., Kapsenberg, M.L. & Kalinski, P. Development of Th1-inducing capacity in myeloid dendritic cells requires environmental instruction. J. Immunol. 164, 4507–4512 (2000). | PubMed | ISI | ChemPort |
23. Corinti, S., Albanesi, C., la Sala, A., Pastore, S. & Girolomoni, G. Regulatory activity of autocrine IL-10 on dendritic cell functions. J. Immunol. 166, 4312–4318 (2001). | PubMed | ISI | ChemPort |
24. Kitamura, H. et al. The natural killer T (NKT) cell ligand -galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J. Exp. Med. 189, 1121–1128 (1999). | Article | PubMed | ISI | ChemPort |
25. Exley, M.A. et al. Cutting edge: Compartmentalization of Th1-like noninvariant CD1d-reactive T cells in hepatitis C virus-infected liver. J. Immunol. 168, 1519–1523 (2002). | PubMed | ISI | ChemPort |
26. Sieling, P.A. et al. Human double-negative T cells in systemic lupus erythematosus provide help for IgG and are restricted by CD1c. J. Immunol. 165, 5338–5344 (2000). | PubMed | ISI | ChemPort |
27. Mailliard, R.B. et al. Complementary dendritic cell–activating function of CD8⁺ and CD4⁺ T cells: helper role of CD8⁺ T cells in the development of T helper type 1 responses. J. Exp. Med. 195, 473–483 (2002). | Article | PubMed | ISI | ChemPort |
28. Gerosa, F. et al. Reciprocal activating interaction between natural killer cells and dendritic cells. J. Exp. Med. 195, 327–333 (2002). | Article | PubMed | ISI | ChemPort |
29. Piccioli, D., Sbrana, S., Melandri, E. & Valiante, N.M. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J. Exp. Med. 195, 335–341 (2002). | Article | PubMed | ISI | ChemPort |
30. Ferlazzo, G. et al. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J. Exp. Med. 195, 343–351 (2002). | Article | PubMed | ISI | ChemPort |
31. Exley, M.A. et al. A major fraction of human bone marrow lymphocytes are Th2-like CD1d-reactive T cells that can suppress mixed lymphocyte responses. J. Immunol. 167, 5531–5534 (2001). | PubMed | ISI | ChemPort |
32. Reinhardt, R.L., Khoruts, A., Merica, R., Zell, T. & Jenkins, M.K. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001). | Article | PubMed | ISI | ChemPort |
33. Masopust, D., Vezys, V., Marzo, A.L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001). | Article | PubMed | ISI | ChemPort |
34. Campbell, J.J. et al. Unique subpopulations of CD56⁺ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J. Immunol. 166, 6477–6482 (2001). | PubMed | ISI | ChemPort |
35. Kim, C.H., Johnston, B. & Butcher, E.C. Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among V24⁺V11⁺ NKT cell subsets with distinct cytokine-producing capacity. Blood 100, 11–16 (2002). | Article | PubMed | ISI | ChemPort |
36. Sallusto, F. et al. Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur. J. Immunol. 29, 1617–1625 (1999). | Article | <