- Open Access
Human γδ T cell Recognition of lipid A is predominately presented by CD1b or CD1c on dendritic cells
© Cui et al; licensee BioMed Central Ltd. 2009
- Received: 17 June 2009
- Accepted: 1 December 2009
- Published: 1 December 2009
The γδ T cells serve as early immune defense against certain encountered microbes. Only a few γδ T cell-recognized ligands from microbial antigens have been identified so far and the mechanisms by which γδ T cells recognize these ligands remain unknown. Here we explored the mechanism of interaction of human γδ T cells in peripheral blood with Lipid A (LA).
First, resting γδ T cells (mainly Vδ2 T cells) displayed a strong proliferative response to LA-pulsed monocyte-derived dendritic cells (moDC) and LA-pulsed paraformaldehyde-fixed moDC, but not to free LA in a TCR γδ-dependent manner. Second, anti-CD1b or anti-CD1c antibodies could block proliferative response of resting γδ T cells to LA-loaded moDC. Besides, only LA-loaded CD1b/CD1c-transfected C1R lymphoblastoma cells (CD1b-/CD1c-C1R) were able to stimulate the proliferation of human γδ T cells. Third, the expressions of both Toll-like receptor (TLR)2 and TLR4 on surface of LA-activated γδ T cells were upregulated, whereas only anti-TLR4 antibody could partially block their response to LA; Finally LA-loaded moDCs induce γδ T cells to produce Th1 cytokines, such as IFN-γ.
Taken together, we found a novel mechanism that human γδ T cells recognize LA in a CD1b- or CD1c-restricted manner in first response against Gram-bacteria, while the interaction between TLR4 on γδ T cells and LA might strengthen the subsequent response of γδ T cells.
This article was reviewed by Hao Shen, Youwen He (nominated by Dr. Laurence C Eisenlohr), Dr. Michael Lenardo and Dr. Pushpa Pandiyan.
- Blocking Assay
- Antibody Blocking Experiment
- CD1c Molecule
- CFSE Dilution Assay
- Recognize Lipid Antigen
Although T cells bearing the TCRγδ represent a minor subset of T cells in the periphery, they are abundant in epithelial and mucosal tissues, the sites of initial host invasion by many pathogens. Many studies demonstrated that TCRγδ+ T cells could have a sentinel role in the early host response against parasitic , bacterial  and viral infections . The γδ T cells can recognize protein antigens in a MHC-unrestricted manner. Moreover, γδ T cells can also recognize non-peptide molecules, such as microbial metabolites (pyrophosphomonoesters and alkyl amines) [4, 5] and synthetic aminobisphosphonates (pamidronate)  directly via TCRγδ. In addition, several studies demonstrated that the interaction of T cells with lipid/glycolipid antigens is associated with MHC-like cluster of differentiation (CD) molecules [7, 8], however, most such experiments have focused on αβ T cells or γδ T cells in mice. The mechanism of human γδ T cells recognizing lipid antigens is largely unknown.
Lipid A (LA) is the most conservative membrane anchor of LPS and is regarded to be responsible for LPS-induced biological effects [9, 10]. The basic structure of LA consists of a β-1, 6-linked glucosamine disaccharide substituted with two negatively charged phosphates and saturated fatty acids. It has strong antigenicity. So we select LA as antigen to further understand the potential biological effect of human γδ T cells in the immune response against invasive bacteria. Here, we want to know whether antigen presenting cells (APCs), such as monocyte-derived dendritic cells (moDC), are able to present LA via CD1 family members to resting γδ T cells (mainly Vδ2 T cells) from peripheral blood. Furthermore, it has been demonstrated that murine γδ T cells could directly interact with LA via Toll like receptor (TLR) 2/4 on their surface [11, 12], so we try to explore the TLR2/4 expression on the surface of human γδ T cells when activated by LA-pulsed moDC.
In present study, we have attempted to address three questions. First, can LA induce human γδ T cells to proliferate in a CD1-restricted manner? Second, which CD1 family member is responsible for LA-induced activation of the γδ T cells? Third, besides TCR, whether LA in the context of CD1 complex activates human γδ T cells via other receptors, such as TLR2/4?
LA-induced proliferation of γδ T cells requires moDC
LA-loaded moDCs induce the proliferation of human γδ T cells
The action of moDCs during LA interaction with human γδ T cells was assessed by means of pulse-fixation experiments. In these experiments, moDCs were pulsed with LA (10 ng/ml) before or after fixation with paraformaldehyde. Cells were extensively washed after LA pulse and therefore there was no free (soluble) antigen present at the time of γδ T-cell addition. As shown in Fig. 2C, the LA-pulsed moDCs before and after fixation were both able to activate γδ T cells and there is no significant difference comparing those without fixation (*P > 0.05 vs nonfixed moDCs). This experiment suggests that LA do stimulate human resting γδ T cells to proliferate by loading on moDCs.
LA recognition by human resting γδ T cells depends on CD1b and CD1c
LA recognition by human resting γδT cells independent of CD1a and CD1d
V δ2+cell-predominant LA-reactive γδ T cells produced Th1, not Th2 cytokines
LA loaded moDCs could induce upregulated expressions of TLR4 and TLR2 on human γδ T cells and the response of LA-activated γδ T cells to LA is associated with TLR4
γδ T cells play an important role in host immune defense and immunoregulation, which have been confirmed to relate to CD1 family. The γδ T cells with Vδ 1 TCR were found to able to recognize self CD1c molecules even in the absence of foreign antigens . These Vδ 1 T cells proliferated in response to CD1+ presenter cells, lysed CD1+ targets, and released Th1 cytokines. Therefore, these cells may directly mediate host defense even before foreign antigen-specific T cells have differentiated. Moreover, these CD1-restricted Vδ 1 T cells can mediate the maturation of DCs via cell-cell contact and cytokine-related (mainly by TNF-α) manners . Besides, CD1 molecules as presenting molecules have been early noted. For example, CD1 molecules are found to be necessary for αβ T cells to recognize lipid antigens . In this context, a purified CD1b-restricted antigen of mycobacterium tuberculosis, mycolic acid, is presented to αβ T cells by CD1b in a TCRαβ-dependent manner. There is also data showing CD1c-mediated T-cell (mainly TCRαβ+ cells) recognition of isoprenoid glycolipids in mycobacterium tuberculosis infection [14, 17]. However, there is no a direct evidence showing human γδ T cells to recognize lipid antigens so far.
In present study, we demonstrate that both CD1b and CD1c molecules on moDC are required for human resting γδ T cells to recognize LA, suggesting that the interaction of human γδ T cell with lipid A is similar to that of αβ T lymphocytes. Consistent with Shamshiev's study , we also identified that LA can be presented by different CD1 molecules (CD1b or CD1c). γδ T cells specific to the same antigen but restricted by different CD1 may be recruited in vivo to different anatomical sites depending on the distribution of CD1+ APC [13, 19, 20].
Our findings demonstrated that recognition of LA by human resting γδ T cells (mainly Vδ2 T cells) depends upon APC, and such recognition is CD1b-/CD1c-dependent and MHC-independent. This conclusion is strongly supported by series of experiments in vitro, especially by antibody blocking assays, proliferative assays using CD1 family molecule-transfected cell lines and pulse-fixation experiments.
CD1 family consists of two groups: group 1 includes CD1a, CD1b and CD1c; group 2 consists of CD1d alone . Several studies [22–24] revealed that the antigen binding sites of CD1 proteins are narrower and deeper than those of MHC molecules and are made up of hydrophobic pockets, which leads to be more adaptive to bind lipid/glycolipid antigens. Our finding raises a question: Why are CD1b and CD1c involved in the presentation of LA for human resting γδ T cells, while CD1a or CD1d is not? Although data from the study of crystallographic structures would explain differences among CD1a, b and d [22–24], further investigation on the function-structure relation is needed to explore the differences among CD1 molecules. Although the crystal structure of CD1c is not clear, we found that the antigen-binding structure between α 1 and α 2 helices of CD1c was more similar to CD1b than to CD1a by computer modeling at the net site http://swissmodel.expasy.org, which is in line with the results obtained from the functional blocking assay. Furthermore, the antibody blocking assay showed that the proliferation of γδ T cells induced by LA-loaded moDC can be almost completely blocked using antibodies against LA and TCRγδ. The result suggests that the recognition of LA by γδ T cell is in a TCRγδ-dependent manner and the epitope of LA recognized by TCRγδ is intact after processed in APC, which was also confirmed by pulse-fixation assay.
Several lines of evidence suggest that murine γδ T cells recognize LPS/LA through TLR2 or TLR4 [25–27]. However, we found that only activated γδ T cells could express both TLR2 and TLR4. It is most important that only TLR4 is much related to LA-loaded moDC-induced proliferation of activated γδ T cells. It seems that activated γδ T cells can recognize LA via TLR4 to magnify their response to LA, which is in agreement with the following report : TLR binding lipid antigens were restricted by the spatial shape of the fatty strain of LA. LA from Escherichia coli that adopts a conical shape induces immune response through TLR4, whereas more cylindrical LA from Porphyromonas gingivalis and so on, induces immune response through TLR2.
In summary, we found a novel mechanism that human γδ T cells recognize LA in a CD1b- or CD1c-restricted manner in first response against Gram-bacteria, while the interaction between TLR4 on γδ T cells and LA might strengthen the subsequent response of γδ T cells.
Antigen and cytokines
LA (Sigma-Aldrich and Alex) was dissolved at a concentration of 2 mg/ml in 0.1% (v/v) triethylamine solution. The solution was diluted with pyrogen-free PBS or culture medium before use. Isopentenyl pyrophosphate (IPP) is also purchased from Sigma Aldrich and used as positive control. Recombinant human IL-2 (Proleukin), GM-CSF (Berlix) and human IL-4 (Berlix) were used in the study.
Cells preparation and reagents
PBMCs were obtained by centrifugation of heparinized peripheral blood from different healthy adult donors over Ficoll-Hypaque gradients (Pharmacia). We had received the local Ethical Committee approval and the informed consent of all participating subjects for this investigation. For preparing moDC, fresh PBMCs (5 × 106 cells/ml) were cultured in 6-well round-bottom microtiter plates (Nunc) for 2 h at 37°C in a humidified atmosphere (5% CO2). Then the adherent and nonadherent cells were collected respectively. After washed with RPMI 1640 medium five times, the adherent cells were cultured for 6-8 days on flat-bottom 6-well plates in RPMI 1640 (Gibco) supplemented with 10% FCS (Biowittaker), L-glutamine (Gibco; 2 mmol/L), 1% penicillin-streptomycin Seromed), GM-CSF (50 ng/ml) and IL-4 (25 ng/ml). The moDC were analyzied by flow cytometry and confirmed by light microscope and electron microscope (data not shown). The purity of moDC was > 90%. The percentages of freshly adherent monocytes cells expressing CD14, CD80 and CD86 were 93 ± 2%, 8 ± 1% and 26 ± 5%, respectively. After 7 days of culture in RPMI medium supplemented with human GM-CSF and IL-4, the moDCs became the major population in adherent cells with high percentages of CD80+ (74 ± 4%) and CD86+ (93 ± 3%) cells. Possible contaminating cells were CD14+ monocytes and macrophages, but the percentage was quite low (< 5%). All moDC were irradiated (4,000 rads).
γδ T cell-enriched population was prepared by deleting TCR αβ+ and CD4+ T cells from nonadherent PBMC using CELLection Dynabeads (Dynal Biotech), while purified resting γδ T cells for proliferation assay were prepared by positive selection using anti-γδ-magnetic beads (Miltenyi Biotec), according to the manufacturer's instructions. Cell viability was confirmed by trypan blue exclusion and forward/side-scatter gating. CD1a-, CD1b-, CD1c or CD1d-transfected C1R lymphoblastoma (CD1a-, CD1b-, CD1c- or CD1d-C1R) cell lines were kindly provided by Dr. Peter Cresswell, Yale University, Connecticut, USA and used for the identification of the responses of human γδ T cells to different CD1 family members. These cells were also irradiated (4,000 rads) before use.
To confirm the quality of moDC, cells were stained by FITC-conjugated anti-CD80, -CD86, -CD1a, CD1b, CD1c, CD1d or -CD14 antibodies (all from Coulter-Immunotech) before and after culture with IL-4 and GM-CSF for 6-8 days. To detect whether there are cross-blocking effects between anti-CD1b and anti-CD1c mAbs, FITC-conjugated anti-CD1b/CD1c mAb was used to stain moDC after blockade by anti-CD1c/CD1b mAb for 2 h (all from Ancell). For evaluation of LA induced-γδ T cell activation,γδ T cell-enriched PBMCs stimulated by LA with or without autologous irradiated moDCs were stained with FITC-conjugated antibody against TCRγδ (Becton Dickinson). To determine the γδ T cell proliferation induced by LA-loaded moDC before and after the antibody blockade, CFSE (2 μM) and phycoerythrin (PE) -conjugated mouse-anti-pan TCRγδ mAb were used. To identify whether freshly isolated/LA-activited γδ T cells express TLR, FITC-conjugated TCRγδ mAb, PE - conjugated anti-pan TLR2 or TLR4 mAb (Becton Dickinson) were used. All the above fluorescence-labeled cells were fixed in PBS with 2% paraformaldehyde and examined using a FACSCalibur flow cytometer (BD Biosciences). Dead cells were excluded on the basis of forward and side light scatter. Data were analyzed using CellQuest or FlowJo software. In all experiments, corresponding isotype-matched mAbs were used as controls.
3H-TdR incorporation, antibody-blocking and cytokine-detecting assays
Purified γδ T cells (purity 1 × 105 cells/well) were plated in triplicates in 96-well flat-bottom plates with or without 4000 rads-irradiated moDCs, CD1a-C1R, CD1b-C1R, CD1c-C1R and CD1d-C1R cells (1 × 104/well) as APCs, in the absence or in the presence of LA of 10 ng/ml. To identify which antigen-presenting molecules are involved in LA induced activation of γδ T cell, purified mAbs (25 μg/ml) against MHC I, MHC II, CD1a, CD1b, CD1c or CD1d (BD Biosciences) were preincubated with these APCs. Anti-TCRγδ mAb was also used as a control. For identification of LA antigenicity, polyclonal antibody (pAb) against LA was preincubated with APCs that had been pulsed with LA for 2 h and then washed extensively. In an additional experiment, for the identification of which TLR on LA-activated γδ T cells is involved in the response to LA and the relationship of CD1b/CD1c with TLR2/TLR4, LA-activated γδ T cells were preincubated with mAbs against TLR2, TLR4, or TLR2 plus TLR4 (BD Biosciences) after resting, respectively. Isotype-matched mAbs were used as controls. To determine if LA need processing by moDCs, moDCs were placed in 96-well plates (1 × 104cells/well) and pulsed with LA. After 4 h, cells were washed with RPMI and incubated with 1% paraformaldehyde for 15 min at room temperature. Plates were washed twice with RPMI before addition of 0.2 M lysine. After 20 min, lysine was discarded and plates were washed four times with RPMI. Alternatively, nonpulsed moDCs were fixed and antigen pulse was performed for 4 h. After pulse were carried out, moDCs were washed extensively and 1 × 105 purified γδ T cells were added to the wells. Cultures were incubated at 37°C in a humidified atmosphere of 5% CO2 in air for 48 h, pulsed with 1 μCi of 3H-TdR during the last 8 h before harvest using a Tomtec harvester (Hamden CT). The filter paper was counted on a Betaplate scintillatin counter (Wallac). To determine cytokine production, before pulsing with 3H-TdR, 50 μl of supernatant in proliferation assay or functional blocking assay was collected from each well. The production of IL-2, IL-4, IL-5, IL-10, IFN-γ and TNF-α was quantified with the CBA Kit according to the manufacturer's instructions (Becton Dickinson). Samples were detected on a flow cytometer (BD FACSCalibur™ flow cytometers) and analyzed through BD CellQuest™ Software.
TCR δ1+ and TCR δ2+subset of LA-reactive γδ T cells
To measure the TCRδ1+ and TCRδ2+ constitution of LA-reactive γδ T cells and their intracellular cytokine production, γδ T cell-enriched PBMCs were co-cultured with LA-pulsed moDCs for 2 weeks. Subsequently, cells were collected and incubated at 3 × 106 cells/tube at room temperature with anti-CD3 antibody and IL-2 for 6 h and Monensin was added for the final 3 h. The cells were then stained with FITC-conjugated TCRδ1+ or TCRδ2+ antibody and fixed in 2% paraformaldehyde. Before adding PE-conjugated anti-IFN-γ mAb (BD PharMingen) or control PE-conjugated mouse IgG1, the cells were permeabilized with 0.5% saponin at RT for 1 h. A gate was set on TCRδ1+ or TCRδ2+ population, and the percentage of IFN-γ positive cells were examined using a FACSCalibur flow cytometer.
Statistical analysis was determined by Student's t test and a P of < 0.05 was considered significant.
Reviewer's report 1
Dr. Hao Shen
Department of Microbiology, U PENN School of Medicine, USA.
In this study, Cui et al. show that lipid A component of LPS is an antigen presented by CD1 on monocyte-derived dendritic cells (DC) to gamma delta (γδ) T-cells. The specificity of human blood γδ T cells is still largely undefined, except for isoprenyl pyrophosphates (IPP) or related, microbial-derived HMB PP, and related artificial compounds. The study by Cui et al. adds lipid A as an alternative ligand for human blood γδ T cells and, therefore, is novel and potentially of substantial interest to γδ T cell research. The experiments supporting their conclusion include γδ T cell proliferation and cytokine secretion in response to lipid A. Furthermore, highly convincing data are presented that show the involvement of CD1b and CD1c in this process. Recognition of IPP or related, microbial-derived HMB PP is in line with the tremendous expansion of this T cell subset in the setting of many microbial infections. Similarly, recognition of lipid A as shown in this study provides further evidence for a role of γδ T cells in microbial infection. These results further our understanding the recognition properties of these important human T cells and their biological function in the context of a role of γδ T cells in innate immune responses.
Two major issues need to be addressed:
Specific point 1
The purity of the lipid A material is of utmost importance for this studies. Any containmination of TLR ligands would compound the interpretation of the results.
We totally agree with the referee that the purity of lipid A is very important, because some phosphoantigens such as HM-PP (or related compounds) that may mixed with the lipid A preparation can induce very strong expansion of γδ T even at very low cencentrations (< nM) and we have repeated the proliferation experiments five times, including three experiments using purified lipid A from Sigma Aldrich and two experiments using the "TLR grade" > 99.9% pure lipid A available from Alexis. The results obtained from all of the experiments are consistent, Lipid A induced significant expansion of γδ T cells in the presence of autologous moDC.
Specific point 2
Since the subset of γδ T cells (i.e., Vd2) activated by lipid A in this study also recognize the phosphoantigen, it would have been very informative to include a standard phosphoantigen such as IPP or BrHPP for comparison. One would expect strong expansion of γδ T cells in response to phosphoantigens in the absence of added DCs (in apparent contrast to lipid A).
Yes, it is really the case. As we expected, IPP indeed induced significantly expansion of purified γδ T cells when we repeated the 3H-TdR incorporation assay using IPP as positive control.
Reviewer's report 2
Dr. Youwen He (nominated by Dr. Laurence C Eisenlohr, Thomas Jefferson University),
Department of Immunology, Duke University Medical Center, USA.
The manuscript by Cui et al has investigated the recognition mechanism of lipid A, an important microbial component, by human gamma delta T cells. The authors first demonstrated that human γδ T cells can be induced to undergo strong proliferation by lipid A pulsed antigen presenting cells. The proliferation of human γδ T cells can be blocked by antibodies against CD1b and CD1c but not CD1a or CD1d. To further investigate the specificity of the interaction, the authors used CD1b or CD1c transfected C1R lymphoblastoma cells as antigen presenting cells. The antibody blocking experiments again demonstrated that CD1b and CD1c play critical roles in presenting lipid A to human γδ T cells to induce cell proliferation. Interestingly, lipid A stimulated human γδ T cells produce a Th2 cytokine profile.
The experiments are well designed and the results are solid. The findings presented in this manuscript are significant in that it has identified a novel mechanism for human γδ T cells in recognition of microbial component. I recommend acceptance of this manuscript.
Specific point 1
The antibody blocking experiments in Figure 2showed that anti-CD1b or CD1c, but not CD1a or CD1d, readily blocked lipid A induced proliferation. Have the authors tested to use a combination of CD1a and CD1d for the blocking assay?
We ever examined the combined blocking function of anti-CD1a and CD1d mAbs through 3H-TdR incorporation assay in our pretest, but just as what they act alone, the proliferation of γδ T cells in this group is not significantly different from the group without any mAb (p > 0.05).
Specific point 2
In Figure 4B, the panel labels (A and B) are not clear. Please change the labels.
Specific point 3
What are the statistic values among the different groups in Figure 5B?
We have made a statistic analysis and corresponding revision in manuscript and Fig. 8 according to the statistic results, which showed that when compared with γδ T cells in the group without any mAb, the proliferation of γδ T cells respectively in the groups with single or both of anti-CD1b and CD1c mAbs, the group with mAbs against CD1b, CD1c, TLR4 and TLR2, or the group with mAb against TLR4 exhibited significant difference (P < 0.05). However, The group with mAb against TLR2 exhibited no significant difference (P > 0.05).
Reviewer's report 3
Dr. Michael Lenardo and Dr. Pushpa Pandiyan,
Molecular Development Section, Laboratory of Immunology, NIH, USA.
The authors have put forward an interesting concept on host immune defense by demonstrating γδ T cell dependent response to lipid antigen bearing bacteria. They deserve credit for presenting a concise report of their findings with clearly presented data. They have demonstrated that recognition of LA by human resting γδ T cells (mainly Vδ2 T cells) depends upon APC, and this recognition is CD1b-/CD1c-dependent and MHC-independent.
There are two important questions that need to be addressed before the manuscript can be published in "Biology Direct" journal.
Because the whole manuscript is based on γδ T cells response to LA, the purity of the starting population of γδ T cells and LA is very crucial.
Specific point 1
The authors have not shown the purity of starting population. By 1 week after stimulation, they are only 23% γδ positive (Fig. 1A). This data raises an important concern of whether the response is an indirect effect on the non γδ T cells that may be expressing TLRs in their culture. The authors should perform at least one experiment showing CFSE dilution of TCR γδ positive cells using highly purified γδ T cells as starting population.
We completely agree with the comments and have made corresponding description in the text now. As shown in Fig 1, TCR γδ expressing cell respectively occupied 4% and 21% in freshly isolated PBMC and γδ T cell-enriched PBMC obtained from depleting TCRαβ+ and CD4+ T cells in the representative donor. We used these γδ T cell-enriched PBMC as starting population in Flow Cytometry analysis and CFSE dilution assay (Fig. 2) to detect the proliferation of human resting γδ T cell induced by LA.
Based on the advice of Dr. Michael Lenardo and Dr. Pushpa Pandiyan, we repeated the CFSE dilution assay using highly purified γδ T cells as starting population (99% purified), although it needs much more fresh blood. The results were consistent with what we previously obtained, indicating that it was the LA-loaded moDCs that induce significant proliferation of human γδ T cells.
Specific point 2
LPS contamination in LA can be addressed easily. For example, the authors should demonstrate how B cells respond to the LA preparations they used.
We had confirmed the purity of Lipid A preparation we used by HPLC and there was no evidence showing molecules like LPS in it. As for the mechanism of B lymphocytes interaction with lipid A, we might dwell on it in a future study project.
On Page 11, the word "Invasing" should be changed to "invading" in the sentence, "....DCs early during microbial invasion, which mediate the adaptive response and effectively.... clear the invasing microbes"
This work is supported by grants (2001CB510009, 2004CB518706 and 2007CB512405) from The National Program for Key Basic Research Project and a grant (NO.30490244) from National Natural Science Foundation of China. The principal funding recipient for all four grants is Dr. Wei He.
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