Macropinocytosis is based on a non-specific uptake of antigens, nutrients, and soluble molecules. This seems to be a dominant mechanism also involved in the uptake of pollen allergens by LCs [ 47 ].
Immature DCs then recognize antigens by membrane-expressed low-specificity receptors such as Toll-like receptors, and interaction of these receptors with their ligand and inflammatory cytokines produced by innate immune response in parallel elicit a complex signaling cascade. This endocytosis is an actin-dependent formation of macropinosomes. The endocytosed antigens are then transferred into early and late endosomes, which fuse with the antigen processing compartments to ensure MHC-II antigen presentation.
Macropinocytosis is a constant sampling process by DCs and is not restricted to an active immune response. In fact, it is the checkpoint for whether an immune response needs to be switched on or peripheral tolerance induction is continued in a healthy status.
Using ovalbumin OVA peptides and exposing them to peripheral plasmacytoid DCs in the thymus led to clonal depletion of OVA-specific thymocytes, thus also contributing to central tolerance [ 48 , 49 ]. In contrast, phagocytosis internalizes large antigens, apoptotic cells, and opsonized pathogens.
The process is initiated by the activation of surface molecules. However, non-specific phagocytosis can also be performed. Antigens are endocytosed by membrane-derived phagosomes and further processed in phagolysosomes. In receptor-mediated endocytosis, specific receptors on the cell surface such as C-type lectin carbohydrate receptors i.
Subsequently, these molecules are transported by clathrin-coated vesicles or non-clathrin-coated vesicles. Upon uncoating of clathrin, antigens are delivered to early endosomes [ 54 ]. Polymorphic MHC-II complexes are formed in antigen processing compartments and subsequently guided to the plasma membrane in order to initiate the antigen-specific immune response via T-cell interaction. Interestingly, lectin receptor-mediated uptake by DCs results in a highly efficient presentation to T cells up to fold increase as compared to antigen internalization via fluid phase [ 55 , 56 ].
In the context of allergic diseases, it is largely unknown what the major differences between healthy and atopic individuals are when being exposed to allergens and sampling by DCs starts. Allergen uptake and processing by DCs is a pivotal step in the induction of Th2 responses. It is known that human DCs are involved in the Th2 sensitization process against common allergens in individuals with genetic predisposition [ 57 ].
The Western life style has been described as a reduced exposure of environmental microbial load to the human immune system. As a consequence, this absence of microbial stimulation could explain why DCs are not instructed to produce IL and fail to counteract Th2 responses. However, other studies suggest that there is no difference in IL production in moDCs between atopic and non-atopic individuals [ 58 ].
A third theory investigated whether allergen exposure levels contribute to an allergic immune response. The first encounter of DCs with allergens can be investigated by using monocyte-derived DCs moDCs obtained from healthy and allergic individuals, respectively. Peripheral blood monocytes are cultured for 7 days with IL-4 and granulocyte macrophage-colony stimulating factor GM-CSF and then exposed to fluorescent-labelled allergens. In vitro, moDCs have been shown to upregulate surface markers i.
When moDCs were incubated with purified HDM and birch pollen allergens Der p 1 and 2, Bet v 1 and subsequently cultured with autologous T cells, they induced predominantly Th2 responses only in the allergic donors, despite similar IL expression levels in both study groups [ 70 , 71 ]. However, recent studies showed that IgE-facilitated uptake is not necessary for Bet v 1 internalization of moDCs [ 69 , 72 ] and blocking endocytic pathways inhibits Bet v 1 uptake [ 72 ].
Interesting results regarding allergen uptake come from Al-Ghouleh et al. They showed that the uptake of the glycosylated allergen Der p 1 is carbohydrate-dependent and was performed via the mannose receptor. Reduction in the uptake due to allergen deglycosylation indicates that glycan moieties play a crucial role in their recognition by innate immune cells, contributing to a downstream activation of Th2 cells and IgE production [ 73 ].
Subsequent processing and lysosomal degradation of allergens is crucial, and the most resistant peptides are then being presented via MHC II molecules to the T cell receptor TCR ; Figure 3. The antigens sampled by DCs are finally processed in late endosomal or lysosomal structures that are enriched in proteolytic enzymes and disulphide reductases [ 74 ].
These proteases are activated by a rather low pH environment. This degradation process is tightly regulated, and includes asparaginyl endopeptidase and cathepsin S. Interestingly, the lysosomal extracts differ in their activity; i. Therefore, DCs can preserve internalized antigens in intact form for some hours in vivo [ 74 ]. Based on recent findings, it seems that individual food allergens—even if they share structural features—display different resistance to DC processing.
As shown by Schulten et al. Cor a 8, from hazelnut, was more rapidly degraded as compared to Pru p 3, the major allergen from peach. A similar observation was found for the birch pollen Bet v 1 homologues from food sources. Dau c 1 from carrot showed remarkable stability as compared to Api g 1 from celery [ 75 ]. To stimulate T-cell receptors TCRs , the terminal sugars have to be removed. Allergen presentation is another crucial task performed by DCs. This process takes place when DCs have reached the T cell zone of the draining lymphoid organ.
However, circulating DCs may also engage other DCs to present the same antigen in the lymph nodes. The transfer occurs either by phagocytosis of the antigen loaded DC [ 77 ] or by the release of antigen-bearing vesicles exosomes [ 78 ]. After migration, DCs stop allergen sampling and start producing a range of chemokines MIP3-b, chemokine C-C motif ligand 18 CCL18 monocyte-derived chemokine, thymus and activation regulated chemokine to attract naive and resting T cells [ 79 ].
In immature cells, new MHC class II molecules accumulate in late endosomes and lysosomes, while in mature DCs, class II molecules are present at the cell surface [ 80 , 81 ].
Upon recognition of the TCR and the interaction of co-stimulatory molecules present on DCs and T cells, signaling activates the respective T cell. Both of them interact with CD28 expressed on the surface of T cells [ 77 , 80 ].
In the recent past, lipids and their potential role during the allergic sensitization process were also investigated. DCs using CD1 proteins are able to present lipid antigens to specific T cells. Two groups of CD1 molecules exist: group 1 consists of CD1a, b, and c molecules, while the CD1d molecule belongs to group 2.
CD1a, b, and c are part of the defense against microbes [ 83 ]. For some allergenic proteins, it has been shown that the food matrix—especially rich in lipids—can affect the immune responses. For example, the food matrix of peanuts was crucial for the immunostimulatory activity of purified peanut allergens.
Only the complete peanut extract induced an increase in cell number, cytokine production, and activation of antigen-presenting cells [ 85 ]. Additionally, in a murine allergy model, for major brazil nut allergen Ber e 1 , a specific lipid fraction was required to induce an allergic immune response [ 86 ].
Finally, Abos-Gracia investigated the effect of lipids obtained from olive pollen on DCs. Upon interaction of the lipid fraction with moDCs, upregulation of surface molecules CD1d and CD86 was observed [ 87 ].
During an allergic response, sampling of allergens leads to a Th2 polarization with subsequent cytokine expression patterns. Therefore, methods to study the uptake, processing, and presentation of individual allergens have been developed to identify the relevant key factors that discriminate between an active Th2-driven response versus a tolerogenic status.
Recent findings suggest that in addition to protein conformation, additional features such as their protease activity, ability to bind lipids, and activation of toll-like receptors contribute to the allergenic potential of certain proteins. Furthermore, the role of matrix components of allergen sources such as lipids and carbohydrates seem to play a role, via the activation of innate immune responses.
Therefore, these detailed studies will provide a better insight into the pathomechanism of Th2-driven immune responses and can elucidate the key points to be addressed for therapeutic actions.
All the authors contributed to this review by literature search, writing and providing input to the respective subsections. Finally all the authors approved the final version. National Center for Biotechnology Information , U. Int J Mol Sci. Published online Jul Author information Article notes Copyright and License information Disclaimer.
Received Jun 5; Accepted Jul 5. This article has been cited by other articles in PMC. Keywords: allergens, dendritic cells, presentation, processing, uptake. Dendritic Cells Are the Most Important Antigen Presenting Cells in Health and Disease Dendritic cells DCs were discovered by Ralph Steinman in , and since then, extensive studies have been performed to characterize the role of different subsets, as extensively summarized in excellent reviews [ 6 , 7 , 8 ].
Open in a separate window. Figure 1. Table 1 Comparative functional analysis of murine and human DCs and their specific surface markers; modified from Reynolds et al. Different Dendritic Cell Subsets Identified in Skin, Respiratory, and Gastrointestinal Tract and Their Role in Allergy Allergic diseases can affect a number of organs, yet skin, respiratory, and gastrointestinal tract are most frequently involved, since they represent the internal and external barrier to environmental antigens.
Figure 2. Figure 3. Conflicts of Interest The authors declare not conflicts of interest. References 1. Global Atlas of Allergy. Radauer C.
Allergens are distributed into few protein families and possess a restricted number of biochemical functions. Allergy Clin. Herz U. Animal models of type I allergy using recombinant allergens.
Zosky G. Animal models of asthma. Allergy J. Bogh K. Current challenges facing the assessment of the allergenic capacity of food allergens in animal models. Banchereau J. Dendritic cells and the control of immunity. Merad M. Origin, homeostasis and function of langerhans cells and other langerin-expressing dendritic cells. Mildner A. Development and function of dendritic cell subsets. Steinman R. Decisions about dendritic cells: Past, present, and future.
Miller J. Deciphering the transcriptional network of the dendritic cell lineage. Bogunovic M. Origin of the lamina propria dendritic cell network.
Schulz O. Randolph G. Tissue-derived molecules also contribute to further promote tissue damage and autoantigen spreading, possibly through pDC-derived Granzyme B secretion. Finally, the therapeutic possibilities based on DC targeting in human autoimmune diseases will be briefly summarized. Publication types Review. It has been proven to be efficient, safe, and tolerable in combination with methotrexate MTX in clinical trials with RA patients when the response to MTX was inadequate Kremer et al.
In Europe, Abatacept is approved for the treatment of patients with highly active and progressive RA, who have never received MTX treatment. It is also approved for the treatment of patients with moderate to severe active RA, who have shown inadequate responses in previous therapies with at least one conventional disease-modifying antirheumatic drug cDMARDs such as MTX or a TNF inhibitor.
In phase III clinical trials, intravenous or subcutaneous injection regimens of Abatacept were beneficial for RA symptoms, disease activity, structural damage progression and physical function of the joint. In a long-term follow-up, the efficacy could be shown to be maintained. The drug-free remission rates following discontinuation of all RA treatment were significantly higher after treatment of Abatacept plus methotrexate than of methotrexate alone.
Intravenous and subcutaneous injections of Abatacept were generally well tolerated and showed low immunogenicity Blair and Deeks, Previous studies using synovial tissue from RA patients treated with Abatacept found the inhibition of B-cell proliferation and down regulation of the expression of B-cell markers Buch et al. Abatacept was also used to treat lupus nephritis by inhibiting CD28 engagement on T cells and plasma cells Bahlis et al.
This mechanistic rationale is strongly supported by the studies in SLE murine models, in which treatment with Abatacept or other forms of CTLA4-Ig have been shown to arrest and even reverse established lupus nephritis. Treatment with Abatacept induced remission by binding to CD80 on renal podocytes in patients with focal segmental glomerulosclerosis Yu et al. Anti CD3 monoclonal antibodies are an immunosuppressant. Tolerance induction by anti-CD3 mAbs is related to the induction of Tregs that control pathogenic autoimmune responses preferentially by inducing anergy or apoptosis in activated T cells while ignoring Tregs You et al.
Biological agents targeting CD3 include teplizumab, otelixizumab, and visilizumab. It has been observed that administration of otelixizumab, teplizumab, or visilizumab result in positive clinical responses Keymeulen et al. Otelixizumab and teplizumab were foremost tested in T1D patients, while visilizumab and foralumab were mainly studied in IBD Yu et al.
In clinical trials, the tolerogenic activity of humanized anti-CD3 mAb visilizumab in T1D was found to be excellent. A phase II trial that assessed the safety and efficacy of visilizumab in patients with severe corticosteroid-refractory ulcerative colitis had promising results Plevy et al. In general, non-FcR binding anti-CD3 mAb are promising models for treatment of autoimmune and inflammatory diseases Herold et al. Furthermore, the Ig part of Alefacept binds to immunoglobulin receptor Fc-gamma-RIII on the surface of natural killer cells and some T cell subpopulations inducing apoptosis of memory T cell subgroups da Silva et al.
A separate anti-LFA-1 antibody Efalizumab has been shown to block adhesive interaction in the treatment of psoriasis. The antibody reduced skin lesions by blocking the adhesion molecule on T cells and was well tolerated and resulted in significant improvement in patients with moderate to severe plaque psoriasis Papp et al.
In summary, the interaction between T cells and DCs involves in the pathogenesis of autoimmune disease. The underlying molecular mechanisms of T cell activation by DCs have been well understood. Three stages during T cells activation by DCs, including antigen presenting, antigen recognition of T cells, and two signals formation have been investigated in great detail.
T cells could be activated in two signals model by simultaneously receiving signal-1 from T-cell recognition of antigen and signal-2 from costimulatory molecular. IS molecular structure is very complex involving in a variety of molecules and signals, which take part in IS formation through interaction and dynamically balance. Understanding the molecular mechanisms of the interaction between T cells and DCs is helpful to discover new drug targets and design immunotherapy strategies that target T cell activation in autoimmune diseases.
These biological drugs show a significant efficacy and have a high safety profile. More biological agents that modulate T cell activation will be developed based on a better understanding of the molecular mechanisms of T cell activation in the near future.
YT and QW collected data and wrote this paper. HK and LZ revised the article. WW designed the work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
National Center for Biotechnology Information , U. Front Pharmacol. Published online Jun Author information Article notes Copyright and License information Disclaimer.
This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology. Received Feb 5; Accepted May The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract The interaction between T cell and dendritic cells DCs that leads to T cell activation affects the progression of the immune response including autoimmune diseases. Keywords: T cell, dendritic cells, activation, autoimmune diseases, immunological synapse, biological agents.
Introduction Various organ specific autoimmune diseases are mediated by an imbalance of T cell subsets, e. Antigen Recognition of T Cells T cell receptor TCR on T cells not only identify peptide-MHC complexes derived from host cells infected by pathogens, but also recognize similar structures derived from healthy host cells, so called autoantigens.
Open in a separate window. Immunotherapy Targeting T Cells Activating in Autoimmune Diseases Detailed insights into the molecular mechanisms of the interaction between T cells and DCs are helpful to design immunotherapy strategies that target T cell activation in autoimmune diseases. Conclusion In summary, the interaction between T cells and DCs involves in the pathogenesis of autoimmune disease. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Footnotes Funding. References Acuto O. Tailoring T-cell receptor signals by proximal negative feedback mechanisms. Peptides 24 — The importance of dendritic cells in maintaining immune tolerance. CDmediated regulation of multiple myeloma cell proliferation and survival. Blood — Dynamic molecular interactions linking the T cell antigen receptor to the actin cytoskeleton. CD1 antigen presentation: how it works. Functional insights on the polarized redistribution of leukocyte integrins and their ligands during leukocyte migration and immune interactions.
Abatacept: a review in rheumatoid arthritis. Drugs 77 — Recruitment and activation of PLCgamma1 in T cells: a new insight into old domains.
EMBO J. Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study. Emerging cell and cytokine targets in rheumatoid arthritis. Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. CD3-specific antibodies: a portal to the treatment of autoimmunity. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation.
The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation.
Diabetes Metab. Advances in CTLAIg-mediated modulation of inflammatory cell and immune response activation in rheumatoid arthritis. Anti-CD3 clinical trials in type 1 diabetes mellitus. CD1a-autoreactive T cells are a normal component of the human alphabeta T cell repertoire.
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