Dendritic Cell Apoptosis: Regulation of Tolerance versus Immunity

Dendritic cell (DC) apoptosis is an important event that regulates the balance between tolerance and immunity through multiple pathways, and defects in DC apoptosis can trigger autoimmunity. DC apoptosis is also associated with immunosuppression and has been observed under several pathologies and infections. Recent studies indicate that apoptotic DCs can also play an active role in induction of tolerance. This review discusses the regulatory pathways of DC apoptosis, stimuli inducing DC apoptosis, and the implications of DC apoptosis in the induction of immunosuppression and/or tolerance.

[1]  Franco Patrone,et al.  The use of dendritic cells in cancer immunotherapy. , 2008, Critical reviews in oncology/hematology.

[2]  K. Siminovitch,et al.  Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg , 2010, European journal of immunology.

[3]  P. Boor,et al.  Prednisolone Suppresses the Function and Promotes Apoptosis of Plasmacytoid Dendritic Cells , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  M. Gutiérrez-López,et al.  Immunological synapse formation inhibits, via NF-κB and FOXO1, the apoptosis of dendritic cells , 2009, Nature Immunology.

[5]  L. Fetler,et al.  Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes. , 2010, Immunity.

[6]  J. Gauldie,et al.  Antigen Presentation by Exosomes Released from Peptide-Pulsed Dendritic Cells Is not Suppressed by the Presence of Active CTL1 , 2007, The Journal of Immunology.

[7]  C. Rabourdin-Combe,et al.  Measles Virus Suppresses Cell-mediated Immunity by Interfering with the Survival and Functions of Dendritic and T Cells , 1997, The Journal of experimental medicine.

[8]  A. Strasser,et al.  Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. , 1999, Science.

[9]  A. Kessel,et al.  The role of T regulatory cells in human sepsis. , 2009, Journal of autoimmunity.

[10]  Simon C Watkins,et al.  Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production. , 2003, Blood.

[11]  M. Viora,et al.  Leptin exerts an anti‐apoptotic effect on human dendritic cells via the PI3K‐Akt signaling pathway , 2009, FEBS letters.

[12]  J. Bluestone,et al.  Control of peripheral T‐cell tolerance and autoimmunity via the CTLA‐4 and PD‐1 pathways , 2008, Immunological reviews.

[13]  R. Steinman,et al.  Trance, a Tumor Necrosis Factor Family Member, Enhances the Longevity and Adjuvant Properties of Dendritic Cells in Vivo , 2000, The Journal of experimental medicine.

[14]  K. Rajewsky,et al.  T Cell–specific Ablation of Fas Leads to Fas Ligand–mediated Lymphocyte Depletion and Inflammatory Pulmonary Fibrosis , 2004, The Journal of experimental medicine.

[15]  J. Lord,et al.  MHC class II‐mediated apoptosis of mature dendritic cells proceeds by activation of the protein kinase C‐δ isoenzyme , 2002 .

[16]  R. Steinman,et al.  TRANCE (Tumor Necrosis Factor [TNF]-related Activation-induced Cytokine), a New TNF Family Member Predominantly Expressed in T cells, Is a Dendritic Cell–specific Survival Factor , 1997, The Journal of experimental medicine.

[17]  R. Testi,et al.  UVB-induced apoptosis of human dendritic cells: contribution by caspase-dependent and caspase-independent pathways. , 2001, Blood.

[18]  A. D'amico,et al.  The Development, Maturation, and Turnover Rate of Mouse Spleen Dendritic Cell Populations , 2000, The Journal of Immunology.

[19]  Tae Woo Kim,et al.  Enhancement of dendritic cell-based vaccine potency by anti-apoptotic siRNAs targeting key pro-apoptotic proteins in cytotoxic CD8(+) T cell-mediated cell death. , 2009, Immunology letters.

[20]  R. Eisenberg,et al.  The lpr and gld genes in systemic autoimmunity: life and death in the Fas lane. , 1992, Immunology today.

[21]  J. Rodríguez-Fernández,et al.  CCR7-Dependent Stimulation of Survival in Dendritic Cells Involves Inhibition of GSK3β1 , 2009, The Journal of Immunology.

[22]  Michael J. Zilliox,et al.  Gene expression patterns in dendritic cells infected with measles virus compared with other pathogens. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[23]  L. Parijs,et al.  A Bcl-2-dependent molecular timer regulates the lifespan and immunogenicity of dendritic cells , 2004, Nature Immunology.

[24]  A. Thomson,et al.  Taming the lions: manipulating dendritic cells for use as negative cellular vaccines in organ transplantation. , 2008, Current opinion in organ transplantation.

[25]  I. Chaudry,et al.  Trauma-hemorrhage induces depressed splenic dendritic cell functions in mice , 2006, The Journal of Immunology.

[26]  R. Consolini,et al.  In vitro treatment of monocytes with 8‐methoxypsolaren and ultraviolet A light induces dendritic cells with a tolerogenic phenotype , 2007, Clinical and experimental immunology.

[27]  M. Jenkins,et al.  Dendritic cell longevity and T cell persistence is controlled by CD154‐CD40 interactions , 2001, European journal of immunology.

[28]  K. Hunt,et al.  Analysis of dendritic cells in tumor-free and tumor-containing sentinel lymph nodes from patients with breast cancer , 2004, Breast Cancer Research.

[29]  Andrea Vondracek,et al.  Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo1 , 2005, The Journal of Immunology.

[30]  Jason A. Skinner,et al.  Induction of TRAIL- and TNF-α-Dependent Apoptosis in Human Monocyte-Derived Dendritic Cells by Microfilariae of Brugia malayi1 , 2008, The Journal of Immunology.

[31]  C. Ardavı́n.  Origin, precursors and differentiation of mouse dendritic cells , 2003, Nature Reviews Immunology.

[32]  Xiaogang Du,et al.  Induction of immature dendritic cell apoptosis by foot and mouth disease virus is an integrin receptor mediated event before viral infection , 2007, Journal of cellular biochemistry.

[33]  K. Siminovitch,et al.  Apoptotic Dendritic Cells Induce Tolerance in Mice through Suppression of Dendritic Cell Maturation and Induction of Antigen-Specific Regulatory T Cells1 , 2009, The Journal of Immunology.

[34]  I. Marzi,et al.  Significant decline of peripheral myeloid dendritic cells following multiple trauma. , 2009, The Journal of surgical research.

[35]  J. Lord,et al.  MHC class II-mediated apoptosis of mature dendritic cells proceeds by activation of the protein kinase C-delta isoenzyme. , 2002, International immunology.

[36]  M. Albert,et al.  Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs , 1998, Nature.

[37]  E. Bröcker,et al.  MHC class II-mediated apoptosis in dendritic cells: a role for membrane-associated and mitochondrial signaling pathways. , 2003, International immunology.

[38]  J. A. Lopez,et al.  Spontaneous apoptosis of blood dendritic cells in patients with breast cancer , 2005, Breast Cancer Research.

[39]  D. Vaux,et al.  CrmA expression in T lymphocytes of transgenic mice inhibits CD95 (Fas/APO‐1)‐transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease. , 1996, The EMBO journal.

[40]  S. Ullrich.  Mechanisms underlying UV-induced immune suppression. , 2005, Mutation research.

[41]  D. Pardoll,et al.  Inhibition of activation-induced death of dendritic cells and enhancement of vaccine efficacy via blockade of MINOR. , 2009, Blood.

[42]  H. Kawai,et al.  Tumor-Derived TGFβ-1 Induces Dendritic Cell Apoptosis in the Sentinel Lymph Node , 2006, The Journal of Immunology.

[43]  K. Tadokoro,et al.  Dendritic cells rapidly undergo apoptosis in vitro following culture with activated CD4+ Vα24 natural killer T cells expressing CD40L , 2001, Immunology.

[44]  D. Littman,et al.  Nuclear Hormone Receptors in T Lymphocytes , 2002, Cell.

[45]  E. Gautier,et al.  Enhanced Dendritic Cell Survival Attenuates Lipopolysaccharide-Induced Immunosuppression and Increases Resistance to Lethal Endotoxic Shock1 , 2008, The Journal of Immunology.

[46]  M. Peter,et al.  Expression of c-FLIP(L) and resistance to CD95-mediated apoptosis of monocyte-derived dendritic cells: inhibition by bisindolylmaleimide. , 2000, Blood.

[47]  H. Kawai,et al.  Tumor-derived TGFbeta-1 induces dendritic cell apoptosis in the sentinel lymph node. , 2006, Journal of immunology.

[48]  Yong‐jun Liu,et al.  Development of dendritic-cell lineages. , 2007, Immunity.

[49]  H. Sandoval,et al.  Dendritic Cell Apoptosis in the Maintenance of Immune Tolerance , 2006, Science.

[50]  Roger Williams,et al.  α-Fetoprotein Impairs APC Function and Induces Their Apoptosis1 , 2004, The Journal of Immunology.

[51]  V. Keshamouni,et al.  The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth. , 2010, Blood.

[52]  T. Moen,et al.  In Vitro Experiments Demonstrate that Monocytes and Dendritic Cells are Rendered Apoptotic by Extracorporeal Photochemotherapy, but Exhibit Unaffected Surviving and Maturing Capacity after 30 Gy Gamma Irradiation , 2008, Scandinavian journal of immunology.

[53]  Charlotte A. Williams,et al.  Apoptotic cells induce dendritic cell‐mediated suppression via interferon‐γ‐induced IDO , 2008 .

[54]  J. Roes,et al.  Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[55]  U. Grohmann,et al.  T cell apoptosis by tryptophan catabolism , 2002, Cell Death and Differentiation.

[56]  O. Eremin,et al.  Dendritic cells are dysfunctional in patients with operable breast cancer , 2004, Cancer Immunology, Immunotherapy.

[57]  Joanna M. Roberts,et al.  CD8+ T Cell-Dependent Elimination of Dendritic Cells In Vivo Limits the Induction of Antitumor Immunity1 , 2000, The Journal of Immunology.

[58]  M. Hengartner.  Apoptosis: DNA destroyers , 2001, Nature.

[59]  L. Bracci,et al.  Type I IFN regulate DC turnover in vivo , 2009, European journal of immunology.

[60]  J. Roes,et al.  Ulcerative colitis and autoimmunity induced by loss of myeloid αv integrins , 2007, Proceedings of the National Academy of Sciences.

[61]  F. Lang,et al.  Sphingomyelinase dependent apoptosis of dendritic cells following treatment with amyloid peptides , 2010, Journal of Neuroimmunology.

[62]  J. Plumas,et al.  Mechanisms of TRAIL-induced apoptosis in leukemic plasmacytoid dendritic cells. , 2006, Experimental hematology.

[63]  G. Mazariegos,et al.  Elevated Myeloid: Plasmacytoid Dendritic Cell Ratio Associates With Early Acute Cellular Rejection in Pediatric Small Bowel Transplantation , 2010, Transplantation.

[64]  D. Schmitt,et al.  Gangliosides from Human Melanoma Tumors Impair Dendritic Cell Differentiation from Monocytes and Induce Their Apoptosis , 2003, The Journal of Immunology.

[65]  Expression of Programmed Death 1 Ligands by Murine T Cells and APC1 , 2002, The Journal of Immunology.

[66]  Sunny Shin,et al.  Rapid Pathogen-Induced Apoptosis: A Mechanism Used by Dendritic Cells to Limit Intracellular Replication of Legionella pneumophila , 2009, PLoS pathogens.

[67]  V. Fadok,et al.  Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. , 2002, The Journal of clinical investigation.

[68]  Markus G. Manz,et al.  Development of Monocytes, Macrophages, and Dendritic Cells , 2010, Science.

[69]  E. Clark,et al.  Regulation of dendritic cell survival and cytokine production by osteoprotegerin , 2009, Journal of leukocyte biology.

[70]  R. Hotchkiss,et al.  Follicular Dendritic Cells Depletion of Splenic Interdigitating and Sepsis Induces Apoptosis and Profound , 2003 .

[71]  M. Foti,et al.  CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation , 2009, Nature.

[72]  C. Elmets,et al.  A Critical Role for the Proapoptotic Protein Bid in Ultraviolet-Induced Immune Suppression and Cutaneous Apoptosis1 , 2008, The Journal of Immunology.

[73]  I. Marzi,et al.  Apoptosis differs in dendritic cell subsets early after severe trauma. , 2009, Human immunology.

[74]  Min Chen,et al.  Deficiency of Bim in dendritic cells contributes to overactivation of lymphocytes and autoimmunity. , 2007, Nature Reviews Immunology.

[75]  S. Wesselborg,et al.  Catalytically active Yersinia outer protein P induces cleavage of RIP and caspase-8 at the level of the DISC independently of death receptors in dendritic cells , 2007, Apoptosis.

[76]  G. Salvesen,et al.  The apoptosome: signalling platform of cell death , 2007, Nature Reviews Molecular Cell Biology.

[77]  Loise M. Francisco,et al.  Immature Dendritic Cells Phagocytose Apoptotic Cells via αvβ5 and CD36, and Cross-present Antigens to Cytotoxic T Lymphocytes , 1998, The Journal of experimental medicine.

[78]  U. Holtick,et al.  Impact of Psoralen/UVA-Treatment on Survival, Activation, and Immunostimulatory Capacity of Monocyte-Derived Dendritic Cells , 2008, Transplantation.

[79]  M. Clare-Salzler,et al.  Extracorporeal photopheresis-induced immune tolerance: a focus on modulation of antigen-presenting cells and induction of regulatory T cells by apoptotic cells , 2009, Current opinion in organ transplantation.

[80]  S. Biocca,et al.  LOX-1 as a natural IFN-alpha-mediated signal for apoptotic cell uptake and antigen presentation in dendritic cells. , 2010, Blood.

[81]  T. Ichim,et al.  Prevention of allograft rejection by in vitro generated tolerogenic dendritic cells. , 2003, Transplant immunology.

[82]  W. Hoetzenecker,et al.  Both pimecrolimus and corticosteroids deplete plasmacytoid dendritic cells in patients with atopic dermatitis. , 2006, The Journal of investigative dermatology.

[83]  Trevor R. F. Smith,et al.  Dendritic Cells Use Endocytic Pathway for Cross-Priming Class Ib MHC-Restricted CD8αα+TCRαβ+ T Cells with Regulatory Properties1 , 2009, The Journal of Immunology.