Diversity in immunological synapse structure

Immunological synapses (ISs) are formed at the T cell-antigen-presenting cell (APC) interface during antigen recognition, and play a central role in T-cell activation and in the delivery of effector functions. ISs were originally described as a peripheral ring of adhesion molecules surrounding a central accumulation of T-cell receptor (TCR)-peptide major histocompatibility complex (pMHC) interactions. Although the structure of these 'classical' ISs has been the subject of intense study, non-classical ISs have also been observed under a variety of conditions. Multifocal ISs, characterized by adhesion molecules dispersed among numerous small accumulations of TCR-pMHC, and motile 'immunological kinapses' have both been described. In this review, we discuss the conditions under which non-classical ISs are formed. Specifically, we explore the profound effect that the phenotypes of both T cells and APCs have on IS structure. We also comment on the role that IS structure may play in T-cell function.     

Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression

We have previously demonstrated that CD4+ CD25+ natural regulatory T cells (Treg cells) induce down-modulation of CD80 and CD86 (B7) molecules on dendritic cells (DCs) in vitro. In this report we show that the extent of down-modulation is functionally significant because Treg-cell conditioned DCs induced poor T-cell proliferation responses. Further, we report that down-modulation was induced rapidly and was inhibited by blocking cytotoxic T lymphocyte antigen-4 (CTLA-4), which is constitutively expressed by the Treg cells. Even though Treg cells have previously been reported to kill antigen-presenting cells, the down-modulation was not due to selective killing of DCs expressing high level of the costimulatory molecules. We propose that Treg cells down-modulate B7-molecules on DCs in a CTLA-4-dependent way, thereby enhancing suppression of T-cell activity.     

Cytotoxic T lymphocyte-associated antigen-4 inhibits integrin-mediated stimulation

The negative role exerted by cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) in the regulation of T-cell activity, as induced by T-cell receptor (TCR)/CD3 and CD28 costimulation, has been widely described. In the present work we investigated the role of CTLA-4 in the control of cell activation, as induced by costimulation of the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) in murine CD4+ T cells. Results show that CTLA-4 engagement inhibits interleukin-2 (IL-2) production, not only when induced by CD3/CD28 costimulation, but also when CD4+ T cells are costimulated by anti-CD3 and anti-LFA-1 monoclonal antibodies (mAbs). LFA-1 has been described to induce Ca2+ mobilization also in the absence of TCR engagement. Moreover, we found that CTLA-4 engagement negatively affects Ca2+ mobilization and NF-AT activation, as induced by LFA-1 engagement alone. PLCgamma1 phosphorylation was also dampened within minutes after CTLA-4 engagement. Altogether these data indicate that through the control of signals induced by different receptors, CTLA-4 could be a global attenuator of T-cell activation.     

Human Naive and Memory T-Helper Cells Display Distinct Adhesion Properties to ICAM-1, LFA-3 and B7 Molecules

In this paper the contribution of different accessory molecules to the adhesion of resting, naive and memory CD4⁺ T cells was examined utilizing a panel of CHO cell transfectants as model antigen-presenting cells (APCs). CD4⁺ T lymphocytes demonstrated strong adhesion to HLA-DR4 transfected CHO cells co-expressing B7, ICAM-I or LFA-3 molecules, suggesting that all three adhesion pathways is utilized by resting CD4⁺ cells. Monoclonal antibodies (MoAbs) against the corresponding receptors on T cells, e.g. anti-CD28, anti-LFA-1β and anti-CD2, inhibited completely T-cell adhesion to natural ligands expressed on transfected CHOcells. Pretreatment of CD4⁺ T cells with NKI-L16 MoAb, which interact with an activation epitope on LFA-loc chain, enhanced adhesion to ICAM-1 but not B7 or LFA-3 expressing CHO cells. Analysis of T helper-cell subsets revealed that memory T cells bound several fold stronger to ICAM-1 expressing transfectants compared to the CD4⁺ 45RA⁺ naive T cells, whereas adhesion to B7, LFA-3- and B7/LFA-3-expressing CHO cells was similar in both T-cell subsets. The kinetics of adhesion of naive and memory CD4⁺ T cells to ICAM-1 was rapid and similar in both subsets. The NKI-L16 MoAb multiplied several times ICAM-1-dependent adhesion in naive compared to memory cells, which enabled the naive cells to reach a similar adhesion level as memory cells. The results suggest that resting naive CD4⁺ T cells utilize preferentially the CD2/LFA-3 or CD28/B7 adhesion pathways upon adhesion to APCs, while memory CD4⁺ T cells utilize the CD2/LFA-3, CD28/B7 and LFA-l/ICAM-1 adhesion pathways. The NK.I-L16 MoAb-induced upregulation of adhesion involves an increased affinity of LFA-1 for its ligand and not a change in the number of LFA-1 molecules. This is compatible with a view that naive cells express a large number of inactive LFA-1 molecules, whereas memory cells express preferentially activated LFA-1 molecules. The inherent low number of active LFA-I molecules on naive CD4⁺ T cells may be important in keeping these cells in a resting state.     

Requirement of the serine at residue 329 for lipid raft recruitment of DNAM-1 (CD226)

Upon antigen recognition by the TCR, leukocyte function-associated antigen-1 (LFA-1) physically associates with the leukocyte adhesion molecule DNAM-1 (CD226), for which the serine phosphorylation at residue 329 (S329) of DNAM-1 plays a critical role. The TCR-mediated signal also induces the formation of the immunological synapse (IS), in which lipid raft-associated molecules, including LFA-1, DNAM-1, protein kinase C, Fyn and others, are recruited, resulting in efficient signal transduction for T cell activation. However, the molecular mechanisms of lipid raft recruitment of many associated molecules have remained unclear. Here, we demonstrate that, while both wild-type (WT) and mutant DNAM-1 at S329 were polarized at the IS, the WT, but not mutant, DNAM-1 associated with lipid rafts at the peripheral supra-molecular activation clusters. We also demonstrate that the association of DNAM-1 with lipid rafts was necessary for the tyrosine phosphorylation of DNAM-1, which is essential for LFA-1-mediated co-stimulatory signaling for naive T cell proliferation and differentiation.     

A novel interface consisting of homologous immunoglobulin superfamily members with multiple functions

Immunoglobulin superfamily (IgSF) members account for a large proportion of cell adhesion molecules that perform important immunological functions, including recognizing a variety of counterpart molecules on the cell surface or extracellular matrix. The findings that CD155/poliovirus receptor (PVR) and CD112/nectin-2 are the ligands for CD226/platelet and T-cell activation antigen 1 (PTA1)/DNAX accessory molecular-1 (DNAM-1), CD96/tactile and Washington University cell adhesion molecule (WUCAM) and that CD226 is physically and functionally associated with lymphocyte function-associated antigen-1 (LFA-1) on natural killer (NK) and activated T cells have largely expanded our knowledge about the functions of CD226, CD96, WUCAM and LFA-1 and their respective ligands, CD155, CD112, intercellular adhesion molecule (ICAM)-1 and junctional adhesion molecule (JAM)-1. The interactions of these receptors and their ligands are involved in many key functions of immune cells including naive T cells, cytotoxic T cells, NK cells, NK T cells, monocytes, dendritic cells, mast cells and platelets/megakaryocytes.     

CTLA-4 interacts with STAT5 and inhibits STAT5-mediated transcription

Cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152) is a member of the immunoglobulin gene superfamily with strong homology to the receptor CD28 with which it shares the ligands CD80 and CD86. Unlike CD28, a potent costimulator of T-cell responses, CTLA-4 is transiently expressed on the cell surface of activated T cells and appears to operate predominantly as a negative regulator of T-cell proliferation. Signal transduction mechanisms utilized by CTLA-4 remain unclear although several mechanisms have been implicated. In this study, we show that the cytoplasmic domain of CTLA-4, but not of CD28, binds to STAT5 in yeast two-hybrid assay and in coimmunoprecipitation assays. Mutations of Tyr165 and Tyr182 in CTLA-4 did not abrogate the interaction of STAT5 with CTLA-4. Finally, the overexpression of CTLA-4 in Jurkat T cells inhibits STAT-mediated activation of STAT5 responsive elements. These results suggest that CTLA-4 and STAT5 interact in T cells and that this interaction is important for CTLA-4 signalling.     

The LFA-3 Adhesion Pathway is Differently Utilized by Superantigen-Activated Human CD4+ T-Cell Subsets

The superantigen SEA binds to MHC class II molecules and activates a large fraction of T cells as a result of interaction with particular TCR-V beta sequences. MHC class II transfected CHO cells induce a marginal CD4+ T-cell proliferation in the presence of SEA. CHO cells transfected with both MHC class II and LFA-3 (HLA-DR4/LFA-3 double transfectants) supported a vigorous T-cell proliferation and required 1000-fold lower SEA concentration than DR4-transfected cells. DR4/LFA-3 double transfectants presenting SEA to CD4+ T cells induced large amounts of IFN-gamma, while single DR4 transfectants failed to elicit IFN-gamma production. CD4+45RA+ naive T cells proliferated much more strongly compared with CD4+45R0+ memory T cells when SEA was presented by the DR4/LFA-3-transfected cells. In contrast, IFN-gamma production was only detected in CD4+45R0+ memory cells. The enhanced proliferation by the CD4+45RA+ naive T cells was not due to a stronger binding to the accessory DR4/LFA-3 cells. Human CD4+ T-cell lines mediated a low level of SEA-dependent cell-mediated cytotoxicity (SDCC) against DR4 target cells, whereas a strong SDCC was mediated against DR4/LFA-3-expressing target cells. These results demonstrate that superantigen-activated human CD4+ T cells require the adhesion molecule LFA-3 for optimal stimulation and that the CD4+ naive and memory T-helper cells are different in their response to LFA-3 as an accessory molecule.     

Costimulation of naive human CD4 T cells through intercellular adhesion molecule-1 promotes differentiation to a memory phenotype that is not strictly the result of multiple rounds of cell division

The process by which naive T cells become activated, differentiate into effector cells and ultimately generate long-lived memory cells is dependent upon a number of factors, including the costimulatory signals received by the T cell. To best understand the multiple events involved, it is important to understand the potential contributions by individual signalling proteins using both in vitro and in vivo studies. Here, the potential for costimulation through intercellular adhesion molecule-1 (ICAM-1; CD54), resident on the surface of naive human T cells, to influence differentiation was investigated. Costimulation of naive T cells through ICAM-1 resulted in expansive cell division, high interleukin-2 production, and protection from apoptosis. Prolonged culture led to outgrowth of a subpopulation of cells with a highly differentiated CD45RA- CD11a(hi) CD27- phenotype. In this respect, costimulation through ICAM-1 was similar to costimulation through CD28 and different from costimulation through leucocyte function-associated antigen-1. The CD45RA- CD11a(hi) CD27- cells responded to suboptimal stimulation through the T-cell receptor alone with a more robust proliferative response compared with naive cells from the same subject. These cells also secreted higher levels of T helper type 1 cytokines in response to lower levels of stimulation than their naive counterparts. The surface phenotype and more sensitive response characteristics suggest the creation of a memory T-cell subpopulation as a result of costimulation through ICAM-1. Finally, generation of this memory population was the result of specific costimulatory signals, and not merely because of a high number of cell divisions. These data reveal a new role for resident ICAM-1 to influence the differentiation of naive T cells.     

Dendritic cells generated in the presence of interferon-alpha stimulate allogeneic CD4+ T-cell proliferation: modulation by autocrine IL-10, enhanced T-cell apoptosis and T regulatory type 1 cells

Dendritic cells (DCs) generated in the presence of IFN-alpha (IFN-DCs) exhibit high expression of major histocompatibility and co-stimulatory molecules and a potent ability to stimulate CD8(+) T-cell responses. Here, we found that IFN-DCs were more potent stimulators of bulk and purified CD8(+) T-cell proliferation, as compared with IL-4-DCs. In contrast, IFN-DCs were less efficient than IL-4-DCs in stimulating allogeneic CD4(+) T-cell proliferation, due to a weak induction of naive CD4(+)CD45RO(-) T-cell proliferation by these DCs. However, both DC populations induced similar levels of proliferation of memory CD4(+)CD45RO(+) T cells. IFN-DCs and IL-4-DCs exhibited a similar phenotype and production of IL-10 following maturation induced by CD40 ligation. In contrast, IFN-DCs produced higher levels of IL-10 during the first days of differentiation. In addition, neutralization of IL-10 during the differentiation of DCs increased the expression of DC-LAMP and MHC class II by IFN-DCs, and the ability of IFN-DCs to stimulate allogeneic CD4(+) T-cell proliferation at similar levels, than IL-4-DCs. Independently of IL-10 production, IFN-DCs were found to induce higher levels of CD4(+)T-cell apoptosis, this effect being more sticking on naive T cells. Finally, we demonstrated that IFN-DCs induced a differentiation bias of naive CD4(+) T cells towards Th1 and Tr1 cells, compared to IL-4-DCs. Taken together, these results indicate that, despite the induction of Tr1 cells and enhanced apoptosis of naive CD4(+) T cells, IFN-DCs are potent stimulators of CD8(+) and memory CD4(+) T cells, and induce a strong polarization of naive CD4(+) T cells towards Th1 cells, further supporting their use in immune-based therapy.     

Small GTPases and LFA-1 reciprocally modulate adhesion and signaling

Summary:  Leukocyte-function-associated antigen-1 (LFA-1) is an integrin that is critical for T-cell adhesion and immunologic responses. As a transmembrane receptor and adhesion molecule, LFA-1 signals bidirectionally, whereby information about extracellular ligands is passed outside-in while cellular activation is transmitted inside-out to the adhesive ectodomain. Here, we review the role of small guanosine triphosphatases (GTPases) in LFA-1 signaling. Rap1, a Ras-related GTPase, appears to be central to LFA-1 function. Rap1 is regulated by receptor signaling [e.g. T-cell receptor (TCR), CD28, and cytotoxic T-lymphocyte antigen-4 (CTLA-4)] and by adapter proteins [e.g. adhesion and degranulation-promoting adapter protein (ADAP) and Src kinase-associated phosphoprotein of 55 kDa (SKAP-55)]. Inside-out signaling flows through Rap1 to regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL) and Rap1-GTP interacting adapter molecule (RIAM) that act in conjunction with the cytoskeleton on the cytosolic domain of LFA-1 to increase adhesion of the ectodomain. Outside-in signaling also relies on small GTPases such as Rho proteins. Vav-1, a guanine nucleotide exchange factor for Rho proteins, is activated as a consequence of LFA-1 engagement. Jun-activating binding protein-1 (JAB-1) and cytohesin-1 have been implicated as possible outside-in signaling intermediates. We have recently shown that Ras is also downstream of LFA-1 engagement: LFA-1 signaling through phospholipase D (PLD) to RasGRP1 was required for Ras activation on the plasma membrane following stimulation of TCR.     

Defective T-lymphocyte signal transduction and function in leukocyte adhesion deficiency

The lymphocyte function-associated antigen-1 (LFA-1) molecule is a cell surface heterodimeric protein that directly mediates cellular adhesion. However, it remains unclear whether LFA-1 molecules are also involved in transmembrane signaling and in the subsequent regulation of cellular functions. Previous attempts to evaluate this issue have been hampered by (1) the ubiquitous expression of LFA-1 on normal lymphoid cells, (2) the limited availability of assays for cellular activation that are not affected by cellular adhesion, and (3) the difficulties in interpreting studies where anti-LFA-1 mAbs are used to alternatively block or stimulate this antigen. In order to avoid these pitfalls, we first isolated and cloned T lymphocytes from a patient with leukocyte adhesion deficiency (LAD), an inherited disorder in which the defective expression of leukocyte integrins results in the production of LFA-1^– T lymphocytes. Different T-cell lines from this patient and from normal individuals were then stimulated through their T-cell antigen receptor complex and were then tested for three aspects of cellular activation: (1) transmembrane signaling (i.e., phospho-inositide turnover), (2) lymphokine secretion (i.e., release of lymphotoxin), and (3) their capacity to mediate cellular cytotoxicity (using murine anti-CD3-producing hybridoma cells as targets). Using assay systems that did not involve LFA-1-mediated adhesion to antigen-presenting cells or target cells, the T-cell lines from the LAD patient were found to be intrinsically defective in all three of these parameters of T cell activation. However, the defects in transmembrane signaling and lymphokine secretion were relative rather than absolute, as the cells were fully responsive to the maximal receptor stimuli provided by immobilized anti-CD3 mAbs or phytohemagglutinin. Our findings suggest that the leukocyte integrins act not only as cellular adhesion molecules, but also directly affect transmembrane signaling during T-cell activation.     

The role of the integrin LFA-1 in T-lymphocyte migration

Summary:  A successful immune response depends on the migration of lymphocytes into lymph nodes or inflamed tissues where they make contact with antigen-presenting cells. We are interested in how one member of the integrin family, leukocyte function-associated antigen-1 (LFA-1), controls the function and, in particular, the migration of immune cells. We find that this integrin operates not only as an adhesion receptor for T lymphoblasts (T cells) but also induces their migration in vitro at approximately 15 μm/min. Migration requires active myosin light chain kinase at the leading edge and Rho kinase at the trailing edge of the cell. Two active conformations of LFA-1 are differently distributed on the T-cell membrane and regulate independent aspects of migration. High-affinity LFA-1 is located in a midcell 'focal zone' and influences the speed of migration, whereas intermediate affinity LFA-1 controls leading edge adhesions. Manipulating LFA-1 conformation in vivo can be performed, for example, by creating the active conformation in a transgenic mouse, and this model gives further insight into the role of LFA-1 in migration. In humans, the beneficial effect of functioning CD18 integrins in combating infections in vivo is illustrated by rare patients displaying two forms of leukocyte adhesion deficiency. In summary, we speculate that T cells have evolved a mode of rapid migration that is of paramount importance in achieving the high-speed immune surveillance upon which depends the body's protection against diverse invaders from pathogens to cancer cells.     

The relation between T-cell expression of LFA-1 and immunological memory.

Antibodies against isotypes of the leucocyte common antigen (LCA, CD45) can be used to identify largely reciprocal subsets of human peripheral T cells, characterized by differential ability to respond to recall antigen in vitro. The transition from naive, unprimed T cells to memory cells capable of responding to recall stimulating has been associated with a switch in surface expression of CD45 from the CD45RA isotype to CD45RO. It has been proposed that this transition is accompanied by the coordinated up-regulation of a number of cell-surface molecules involved in cellular adhesion and/or activation, including the leucocyte function-associated antigens (LFA). In the present study we have examined the expression of LFA-1 on subsets of human peripheral T cells, and related it to the expression of markers of cellular activation and CD45 isotypes, and thus to immunological memory. Our results suggest that the intensity of LFA-1 expression on the surface membrane of human peripheral T cells is not tightly associated with maturation status as judged by LCA isotype expression, but rather reflects the degree of cellular activation. This conclusion is supported by data of T-cell function in vitro, showing similar antigen- and mitogen-induced proliferative responses in T-cell subsets characterized by low as well as high surface expression of LFA-1.     

Jagged1-expressing adenovirus-infected dendritic cells induce expansion of Foxp3+ regulatory T cells and alleviate T helper type 2-mediated allergic asthma in mice

Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in directing T-cell responses. Regulatory T (Treg) cells possess an immunosuppressive ability to inhibit effector T-cell responses, and Notch ligand Jagged1 (Jag1) is implicated in Treg cell differentiation. In this study, we evaluated whether bone marrow-derived DCs genetically engineered to express Jag1 (Jag1-DCs) would affect the maturation and function of DCs in vitro and further investigated the immunoregulatory ability of Jag1-DCs to manipulate T helper type 2 (Th2) -mediated allergic asthma in mice. We produced Jag1-DCs by adenoviral transduction. Overexpression of Jag1 by ovalbumin (OVA) -stimulated Jag1-DCs exhibited increased expression of programmed cell death ligand 1 (PD-L1) and OX40L molecules. Subsequently, co-culture of these OVA-pulsed Jag1-DCs with allogeneic or syngeneic CD4⁺ T cells promoted the generation of Foxp3⁺ Treg cells, and blocking PD-L1 using specific antibodies partially reduced Treg cell expansion. Furthermore, adoptive transfer of OVA-pulsed Jag1-DCs to mice with OVA-induced asthma reduced allergen-specific immunoglobulin E production, airway hyperresponsiveness, airway inflammation, and secretion of Th2-type cytokines (interleukin-4, interleukin-5, and interleukin-13). Notably, an increased number of Foxp3⁺ Treg cells associated with enhanced levels of transforming growth factor-β production was observed in Jag1-DC-treated mice. These data indicate that transgenic expression of Jag1 by DCs promotes induction of Foxp3⁺ Treg cells, which ameliorated Th2-mediated allergic asthma in mice. Our study supports an attractive strategy to artificially generate immunoregulatory DCs and provides a novel approach for manipulating Th2 cell-driven deleterious immune diseases.     

Transient Depletion of T Cells with Bright CD11a/CD18 Expression from Peripheral Circulation during Acute Kawasaki Disease

To clarify the activation of peripheral blood T cells in Kawasaki disease (KD) patients, we investigated whether expression of lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) and/or intercellular adhesion molecule-1 (ICAM-1, CDS4) on peripheral blood T cells increases during the acute stage. Expression of cellular adhesion molecules was measured using flow cytometry. There was a decrease in the percentage of CD3⁺ T cells in the bright LFA-1α and LFA-1β population and a concomitant increase in the dim population of LFA-1α and LFA-1β during the acute stage, in comparison with those of the convalescent stage. In addition, we observed no significant differences in ICAM-1 expression during the acute stage compared with that of the convalescent stage. In our view the present data, in conjunction with previous reports on T-cell function during acute KD, suggest that activated T cells are temporarily withdrawn from peripheral circulation during acute KD.     

Accessory molecule regulation of naive CD4 T cell activation

Naive CD4 T cell activation is a complex process involving many steps. T cell receptor (TCR) signals, provided by interaction with peptide/MHC on antigen-presenting cells (APC), control many events associated with activation. The extent of TCR signaling and the magnitude of the T cell response is in turn controlled by accessory molecules on APC, which stabilize T-APC interactions. Full T cell activation additionally requires multiple costimulatory signals, generated upon ligation of T cell coreceptors by accessory molecules, and these lead to IL-2 production, proliferation and differentiation of the naive cell into an effector state. This review summarizes the role played by accessory molecules in naive CD4 activation and discusses how integration of signals from these molecules, with signals from the TCR, may determine the outcome of T-APC interaction. The available data provide explanations for why only APC which express high levels of multiple costimulatory/adhesion molecules, such as dendritic cells and activated B cells, induce efficient naive T cell responses, and suggest that ICAM-1/LFA-1 and B7/CD28 interactions are major pathways used to initiate naive T cell activation.     

Differential Expression Of Adhesion Molecules Within The Human Thymus

Development of a diverse, MHC-restricted yet self-tolerant T-cell repertoire occurs within the thymus, and requires contact between developing T cells and their stromal microenvironment. Such interactions are likely to depend on the combinatorial effect of specific adhesion molecules. As a preliminary step to determining their role in T-cell development, we have studied the distribution of LFA-1/ICAM-1, CD2/LFA-3, VLA-4/VCAM-1, and HECA 452-antigen/E-Selectin ligand pairs on frozen sections of human thymus. Using two color-immunohistochemistry, and a variety of cell-lineage markers that reveal the nature of the cells on which these adhesion molecules are located, we find a differential distribution of adhesion molecules, with some being shared by both endothelial and epithelial cells. We also identify the VCAM-1-positive subpopulation as cortical macrophages. The relevance of these findings to thymopoiesis is discussed.     

Apoptotic cell capture by DCs induces unexpectedly robust autologous CD4+ T‐cell responses

Apoptotic cells represent an important source of self‐antigens and their engulfment by dendritic cells (DCs) is usually considered to be related to tolerance induction. We report here an unexpectedly high level of human CD4⁺ T‐cell proliferation induced by autologous DCs loaded with autologous apoptotic cells, due to the activation of more than 10% of naive CD4⁺ T cells. This proliferation is not due to an increase in the costimulatory capacity of DCs, but is dependent on apoptotic cell‐associated material processed through an endo‐lysosomal pathway and presented on DC MHC class II molecules. Autologous CD4⁺ T cells stimulated with apoptotic cell‐loaded DCs exhibit suppressive capacities. However, in the presence of bacterial lipopolysaccharide, apoptotic cell‐loaded DCs induce the generation of IL‐17‐producing cells. Thus, apoptotic cell engulfment by DCs may lead to increased autologous responses, initially generating CD4⁺ T cells with suppressive capacities able to differentiate into Th17 cells in the presence of a bacterial danger signal such as LPS.