Tolerogenic dendritic cells (a. k. a. tol-DCs, tDCs, or DCregs) are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs.[1] Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.

Tol-DCs are not lineage specific and their immune-suppressive functions is due to their state of activation and/or differentiation. Generally, properties of all types of dendritic cells can be highly affected by local micro-environment such as presence of pro or anti-inflammatory cytokines, therefore tolerogenic properties of tol-DCs are often context dependant and can be even eventually overridden into pro-inflammatory phenotype.[2][3][4]

Tolerogenic DCs present a potential strategy for treatment of autoimmune diseases, allergic diseases and transplant rejections. Moreover, Ag-specific tolerance in humans can be induced in vivo via vaccination with Ag-pulsed ex vivo generated tolerogenic DCs.[5] For that reason, tolerogenic DCs are an important promising therapeutic tool.[6]

Dendritic cells

Dendritic cells (DCs) were first discovered and described in 1973 by Ralph M.  Steinman. They represent a bridge between innate and adaptive immunity and play a key role in the regulation of initiation of immune responses. DCs populate almost all body surfaces and they do not kill the pathogens directly, they utilize and subsequently degrade antigens to peptides by their proteolytic activity. After that, they present these peptides in complexes together with their MHC molecules on their cell surface. DCs are also the only cell type which can activate naïve T cells and induce antigen-specific immune responses.[6][7]

Therefore, their role is crucially important in balance between tolerance and immune response.

Tolerogenic dendritic cells

Tolerogenic DCs are essential in maintenance of central and peripheral tolerance through induction of T cell clonal deletion, T cell anergy and generation and activation of regulatory T (Treg) cells. For that reason, tolerogenic DCs are possible candidates for specific cellular therapy for treatment of allergic diseases, autoimmune diseases (e.g. type 1 diabetes, multiple sclerosis, rheumatoid arthritis) or transplant rejections.[8][9][6]

Tolerogenic DCs often display an immature or semi-mature phenotype with characteristically low expression of costimulatory (e.g. CD80, CD86) and MHC molecules on their surface. Tolerogenic DCs also produce different cytokines as mature DCs (e.g. anti-inflammatory cytokines interleukin (IL)-10, transforming growth factor-β (TGF-β)). Moreover, tolerogenic DCs may also express various inhibitory surface molecules (e.g. programmed cell death ligand (PDL)-1, PDL-2) or can modulate metabolic parameters and change T cell response. For example, tolerogenic DCs can release or induce enzymes such as indoleamine 2,3-dioxygenase (IDO) or heme oxygenase-1 (HO-1). IDO promotes the degradation of tryptophan to N-formylkynurenin leading to reduced T cell proliferation, whereas HO- 1 catalyzes degradation of hemoglobin resulting in production of monoxide and lower DC immunogenicity. Besides that, tolerogenic DCs also may produce retinoic acid (RA), which induces Treg differentiation.[10][11]

Human tolerogenic DCs may be induced by various immunosuppressive drugs or biomediators. Immunosuppressive drugs, e.g. corticosteroid dexamethasone, rapamycin, cyclosporine or acetylsalicylic acid, cause low expression of costimulatory molecules, reduced expression of MHC, higher expression of inhibitory molecules (e.g. PDL-1) or higher secretion of IL-10 or IDO. In addition, incubation with inhibitory cytokines IL-10 or TGF-β leads to generation of tolerogenic phenotype. Other mediators also affect generation of tolerogenic DC, e.g. vitamin D3, vitamin D2,[12] hepatocyte growth factor or vasoactive intestinal peptide. The oldest and mostly used cytokine cocktail for in vitro DC generation is GM-CSF/IL-4.[10][5]

Tolerogenic DCs may be a potential candidate for specific immunotherapy and are studied for using them for treatment of inflammatory, autoimmune and allergic diseases and also in transplant medicine. Important and interesting feature of tolerogenic DCs is also the migratory capacity toward secondary lymph organs, leading to T-cell mediated immunosuppression. The first trial to transfer tolerogenic DCs to humans was undertaken by Ralph Steinman's group in 2001. Relating to the DC administration, various application have been used in humans in last years. Tolerogenic DCs have been injected e.g. intraperitoneally in patients with Crohn's disease, intradermally in diabetes and rheumatoid arthritis patients, subcutaneously in rheumatoid arthritis patients and via arthroscopic injections in joints of patient with rheumatoid and inflammatory arthritis.[13]

Therefore, it is necessary to test tolerogenic DCs for a stable phenotype to exclude a loss of the regulatory function and a switch to an immunostimulatory activity.

Characteristic surface molecules

Despite tol-DCs not being lineage specific, they generally express more cell-surface immuno-suppressive molecules and factors in comparison with immunogenic co-stimulatory molecules. Higher expression of inhibitory molecules is associated with their tolerogenic abilities.

These molecules are: PD-L1, immunoglobulin like transcripts ILT (ILT3/4/5), B7-H1, SLAM, DEC-205.[14][15][16][17] Tolerogenic effect has been demonstrated also by over-expression of Jagged-1 on DCs which in turn induced antigen specific T regulatory cells producing TGF-b.[18]

Mechanism of tolerogenicity

Tol-DCs promotes central and peripheral tolerance. These tolerogenic properties are executed by deletion of T cells, induction of Tregs and anergized T cells, then by expression of immunomodulatory molecules such as PD-L1 and PD-L2, heme oxygenase 1, HLA-G, CD95L, TNF-related apoptosis inducing ligands, galectin-1 and DC-SIGN and production of immunosuppressive molecules such as IL-10, TGF-b, indoleamine 2,3-dioxygenase (IDO), IL-27 and NO.[19][20][21][22]

Cytokines and molecules in differentiation of tol-DCs

Tol-DCs can be induced by various stimuli. It has been shown that following molecules induce/promote/favour induction of tol-DCs: IL-10, IL-27, TGF-b1, hepatocyte growth factor, vasoactive intestinal peptide, retinoid acid, vitamin D3, corticosteroids, rapamycin, cyclosporine, tacrolism, aspirin and ligands of AhR.[23][24]

Tolerance-inducing vaccination

Currently are characterized two subpopulations of human tolerogenic DCs: CD83highCCR7+ and CD83lowCCR7− IL-10DCs. CD83high IL-10DCs display a stable phenotype under inflammatory conditions and show higher migratory capacity, providing migration to secondary lymphoid organs. Therefore, CD83high IL-10DCs could be promising and great candidates for tolerance-inducing vaccination studies in vivo.[5]

In 2011, Giannoukakis et al. published results of randomized, double-blind phase I study of autologous DCs vaccination in type I diabetic patients. Treatment with these cells was safe and well tolerated.[25]

Populations of tolerogenic dendritic cells

The whole pool of tolerogenic dendritic cells can be divided in two large groups - Naturally occurring tolerogenic DCs and induced tolerogenic DCs.

Naturally occurring tolerogenic dendritic cells.

Natural tol-DCs are mostly present in site of tolerogenic environment. They are maintained in their tolerogenic state by anti-inflammatory cytokines presented in those environments, but they can be easily overridden by inflammatory signals into being immunogenic.[23] They can be found in intestinal, pulmonary, cutaneous, blood and hepatic tissues. It is yet expected they will be found even elsewhere.[3]

Immature and semimature dendritic cells (iDCs) with tolerogenic properties

Their tolerogenic effect is mostly due to their lack of immunogenic co-stimulatory molecules despite their ability to present antigens. This phenomenon results in T cells anergy.[3] Repetitive stimulation of T cells by iDCs can convert them into Tregs[26][27] Immature and semimature dendritic cells are tolerogenic under steady-state conditions and once exposed to pro-inflammatory milieu they can also become immunogenic.[28][29]

Induced tolerogenic dendritic cells

Tol-DCs can be induced by chemicals, pathological conditions or molecular modifications.

Pathogen-induced tolerogenic DC

Certain pathogens are capable of hijacking host immune tolerance and induce Tregs in their surroundings.[30][31][32]

Tumour-induced tolerogenic DC

Tumours also developed ways of inducing tol-DCs resulting in differentiation and accumulation of Tregs in their stroma and draining lymph node.[33][34]

Pharmacologically-induced tolerogenic DCs

As already mentioned above many pharmacological substances are capable of inducing tol-DCs including corticosteroids, rapamycin, cyclosporine, tacrolism, aspirin,.

Genetically-induced tolerogenic DCs

Genetic manipulations can used to confer tolerogenic properties on DCs such as gene knock down, knock-out, transgenic over expression of proteins and others.[35]

References

  1. ↑ Hill M, Cuturi MC (December 2010). "Negative vaccination by tolerogenic dendritic cells in organ transplantation". Current Opinion in Organ Transplantation. 15 (6): 738–43. doi:10.1097/MOT.0b013e32833f7114. PMID 20881497. S2CID 26035030.
  2. ↑ Wu L, Liu YJ (June 2007). "Development of dendritic-cell lineages". Immunity. 26 (6): 741–50. doi:10.1016/j.immuni.2007.06.006. PMID 17582346.
  3. 1 2 3 Maldonado RA, von Andrian UH (2010). How tolerogenic dendritic cells induce regulatory T cells. Advances in Immunology. Vol. 108. pp. 111–65. doi:10.1016/B978-0-12-380995-7.00004-5. ISBN 9780123809957. PMC 3050492. PMID 21056730.
  4. ↑ Raker VK, Domogalla MP, Steinbrink K (2015-11-09). "Tolerogenic Dendritic Cells for Regulatory T Cell Induction in Man". Frontiers in Immunology. 6: 569. doi:10.3389/fimmu.2015.00569. PMC 4638142. PMID 26617604.
  5. 1 2 3 Kryczanowsky, Fanny; Raker, Verena; Graulich, Edith; Domogalla, Matthias P.; Steinbrink, Kerstin (2016-11-01). "IL-10–Modulated Human Dendritic Cells for Clinical Use: Identification of a Stable and Migratory Subset with Improved Tolerogenic Activity". The Journal of Immunology. 197 (9): 3607–3617. doi:10.4049/jimmunol.1501769. ISSN 0022-1767. PMID 27683749.
  6. 1 2 3 Domogalla, Matthias P.; Rostan, Patricia V.; Raker, Verena K.; Steinbrink, Kerstin (2017). "Tolerance through Education: How Tolerogenic Dendritic Cells Shape Immunity". Frontiers in Immunology. 8: 1764. doi:10.3389/fimmu.2017.01764. ISSN 1664-3224. PMC 5770648. PMID 29375543.
  7. ↑ Kalantari, Tahereh; Kamali-Sarvestani, Eskandar; Ciric, Bogoljub; Karimi, Mohamad H.; Kalantari, Mohsen; Faridar, Alireza; Xu, Hui; Rostami, Abdolmohamad (2011-11-22). "Generation of immunogenic and tolerogenic clinical-grade dendritic cells". Immunologic Research. 51 (2–3): 153–160. doi:10.1007/s12026-011-8255-5. ISSN 0257-277X. PMC 3474330. PMID 22105838.
  8. ↑ Hilkens, C. M. U.; Isaacs, J. D. (2013-04-10). "Tolerogenic dendritic cell therapy for rheumatoid arthritis: where are we now?". Clinical & Experimental Immunology. 172 (2): 148–157. doi:10.1111/cei.12038. ISSN 0009-9104. PMC 3628318. PMID 23574312.
  9. ↑ Bell, G. M.; Anderson, A. E.; Diboll, J.; Reece, R.; Eltherington, O.; Harry, R. A.; Fouweather, T.; MacDonald, C.; Chadwick, T. (2017-01-01). "Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis". Annals of the Rheumatic Diseases. 76 (1): 227–234. doi:10.1136/annrheumdis-2015-208456. ISSN 0003-4967. PMC 5264217. PMID 27117700.
  10. 1 2 Hubo, Mario; Trinschek, Bettina; Kryczanowsky, Fanny; Tuettenberg, Andrea; Steinbrink, Kerstin; Jonuleit, Helmut (2013-04-03). "Costimulatory Molecules on Immunogenic Versus Tolerogenic Human Dendritic Cells". Frontiers in Immunology. 4: 82. doi:10.3389/fimmu.2013.00082. ISSN 1664-3224. PMC 3615188. PMID 23565116.
  11. ↑ Domogalla, Matthias P.; Rostan, Patricia V.; Raker, Verena K.; Steinbrink, Kerstin (2017-12-11). "Tolerance through Education: How Tolerogenic Dendritic Cells Shape Immunity". Frontiers in Immunology. 8: 1764. doi:10.3389/fimmu.2017.01764. ISSN 1664-3224. PMC 5770648. PMID 29375543.
  12. ↑ Funda, David P.; Goliáš, Jaroslav; Hudcovic, Tomáš; Kozáková, Hana; Špíšek, Radek; Palová-Jelínková, Lenka (2018). "Antigen Loading (e.g., Glutamic Acid Decarboxylase 65) of Tolerogenic DCs (tolDCs) Reduces Their Capacity to Prevent Diabetes in the Non-Obese Diabetes (NOD)-Severe Combined Immunodeficiency Model of Adoptive Cotransfer of Diabetes As Well As in NOD Mice". Frontiers in Immunology. 9: 290. doi:10.3389/fimmu.2018.00290. ISSN 1664-3224. PMC 5820308. PMID 29503651.
  13. ↑ Hilkens, C M U; Isaacs, J D (May 2013). "Tolerogenic dendritic cell therapy for rheumatoid arthritis: where are we now?". Clinical and Experimental Immunology. 172 (2): 148–157. doi:10.1111/cei.12038. ISSN 0009-9104. PMC 3628318. PMID 23574312.
  14. ↑ Smits HH, de Jong EC, Wierenga EA, Kapsenberg ML (March 2005). "Different faces of regulatory DCs in homeostasis and immunity". Trends in Immunology. 26 (3): 123–9. doi:10.1016/j.it.2005.01.002. PMID 15745853.
  15. ↑ Cella M, Döhring C, Samaridis J, Dessing M, Brockhaus M, Lanzavecchia A, Colonna M (May 1997). "A novel inhibitory receptor (ILT3) expressed on monocytes, macrophages, and dendritic cells involved in antigen processing". The Journal of Experimental Medicine. 185 (10): 1743–51. doi:10.1084/jem.185.10.1743. PMC 2196312. PMID 9151699.
  16. ↑ Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M (March 2005). "Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4" (PDF). Nature Immunology. 6 (3): 280–6. doi:10.1038/ni1165. PMID 15685176. S2CID 11666646.
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  18. ↑ Yvon ES, Vigouroux S, Rousseau RF, Biagi E, Amrolia P, Dotti G, Wagner HJ, Brenner MK (November 2003). "Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells". Blood. 102 (10): 3815–21. doi:10.1182/blood-2002-12-3826. PMID 12842995.
  19. ↑ Ezzelarab M, Thomson AW (August 2011). "Tolerogenic dendritic cells and their role in transplantation". Seminars in Immunology. 23 (4): 252–63. doi:10.1016/j.smim.2011.06.007. PMC 3192911. PMID 21741270.
  20. ↑ Xia S, Guo Z, Xu X, Yi H, Wang Q, Cao X (October 2008). "Hepatic microenvironment programs hematopoietic progenitor differentiation into regulatory dendritic cells, maintaining liver tolerance". Blood. 112 (8): 3175–85. doi:10.1182/blood-2008-05-159921. PMC 2569171. PMID 18669892.
  21. ↑ Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, Vermeulen ME, Geffner JR, Rabinovich GA (September 2009). "Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10". Nature Immunology. 10 (9): 981–91. doi:10.1038/ni.1772. hdl:11336/78711. PMID 19668220. S2CID 24418718.
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  23. 1 2 Gordon JR, Ma Y, Churchman L, Gordon SA, Dawicki W (2014-01-31). "Regulatory dendritic cells for immunotherapy in immunologic diseases". Frontiers in Immunology. 5: 7. doi:10.3389/fimmu.2014.00007. PMC 3907717. PMID 24550907.
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  25. ↑ Giannoukakis, Nick; Phillips, Brett; Finegold, David; Harnaha, Jo; Trucco, Massimo (2011-09-01). "Phase I (Safety) Study of Autologous Tolerogenic Dendritic Cells in Type 1 Diabetic Patients". Diabetes Care. 34 (9): 2026–2032. doi:10.2337/dc11-0472. ISSN 0149-5992. PMC 3161299. PMID 21680720.
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  34. ↑ Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, Kroemer G, Martin F, Chauffert B, Zitvogel L (October 2005). "Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation". The Journal of Experimental Medicine. 202 (7): 919–29. doi:10.1084/jem.20050463. PMC 2213166. PMID 16186184.
  35. ↑ Morelli AE, Thomson AW (August 2007). "Tolerogenic dendritic cells and the quest for transplant tolerance". Nature Reviews. Immunology. 7 (8): 610–21. doi:10.1038/nri2132. PMID 17627284. S2CID 6587584.
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