Induction of Treg by monocyte‐derived DC modulated by vitamin D3 or dexamethasone: Differential role for PD‐L1

Specific therapy with modulated DC may restore immunological tolerance, thereby obviating the need for chronic immunosuppression in transplantation or autoimmunity. In this study we compared the tolerizing capacity of dexamethasone (Dex)‐ and 1α,25‐dihydroxyvitamin D3 (VD3)‐modulated DC. Treatment of monocytes with either VD3 or Dex resulted in DC with stable, semi‐mature phenotypes compared with standard DC, with intermediate levels of co‐stimulatory and MHC class II molecules, which remained unaltered after subsequent pro‐inflammatory stimulation. IL‐12p70 secretion was lost by VD3‐ and Dex‐DC, whereas IL‐10 secretion was unaffected. VD3‐DC distinctly produced large amounts of TNF‐α. Both VD3‐ and Dex‐DC possessed the capacity to convert CD4 T cells into IL‐10‐secreting Treg potently suppressing the proliferation of responder T cells. However, only Treg induced by VD3‐DC exhibited antigen specificity. VD3‐, but not Dex‐, DC expressed significant high levels of PD‐L1 (programmed death‐1 ligand), upon activation. Blockade of PD‐L1 during priming redirected T cells to produce IFN‐γ instead of IL‐10 and abolished acquisition of regulatory capacity. Our findings demonstrate that both VD3‐ and Dex‐DC possess durable but differential tolerogenic features, acting via different mechanisms. Both are potentially useful to specifically down‐regulate unwanted immune responses and induce immune tolerance. These modulated DC appear suitable as adjuvant in antigen‐specific clinical vaccination intervention strategies.

[1]  L. Nagy,et al.  1,25-Dihydroxyvitamin D3 Is an Autonomous Regulator of the Transcriptional Changes Leading to a Tolerogenic Dendritic Cell Phenotype12 , 2009, The Journal of Immunology.

[2]  John H. Robinson,et al.  Lps Activation Is Required for Migratory Activity and Antigen Presentation by Tolerogenic Dendritic Cells , 2022 .

[3]  C. Benedict,et al.  Dendritic Cell Programming by Cytomegalovirus Stunts Naive T Cell Responses via the PD-L1/PD-1 Pathway1 , 2008, The Journal of Immunology.

[4]  G. Mazariegos,et al.  High PD-L1/CD86 Ratio on Plasmacytoid Dendritic Cells Correlates With Elevated T-Regulatory Cells in Liver Transplant Tolerance , 2008, Transplantation.

[5]  D. Hommes,et al.  Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. , 2007, Immunity.

[6]  Kathleen M. Smith,et al.  Development, cytokine profile and function of human interleukin 17–producing helper T cells , 2007, Nature Immunology.

[7]  T. Huizinga,et al.  Immunomodulatory Dendritic Cells Inhibit Th1 Responses and Arthritis via Different Mechanisms1 , 2007, The Journal of Immunology.

[8]  T. Okazaki,et al.  PD-1 and PD-1 ligands: from discovery to clinical application. , 2007, International immunology.

[9]  Yi-bei Zhu,et al.  Expression of programmed-death receptor ligands 1 and 2 may contribute to the poor stimulatory potential of murine immature dendritic cells. , 2007, Immunobiology.

[10]  M. Leach,et al.  PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis , 2007, Journal of Neuroimmunology.

[11]  L. Adorini,et al.  1,25-Dihydroxyvitamin D3 Selectively Modulates Tolerogenic Properties in Myeloid but Not Plasmacytoid Dendritic Cells1 , 2007, The Journal of Immunology.

[12]  M. Willart,et al.  Contribution of the PD‐1 ligands/PD‐1 signaling pathway to dendritic cell‐mediated CD4+ T cell activation , 2006, European journal of immunology.

[13]  O. Beretta,et al.  Effects of dexamethazone on LPS‐induced activationand migration of mouse dendritic cells revealed by a genome‐wide transcriptional analysis , 2006, European journal of immunology.

[14]  G. Adema,et al.  Dendritic Cells Activated by Lipopolysaccharide after Dexamethasone Treatment Induce Donor-Specific Allograft Hyporesponsiveness , 2006, Transplantation.

[15]  G. Freeman,et al.  Tissue expression of PD-L1 mediates peripheral T cell tolerance , 2006, The Journal of experimental medicine.

[16]  Giuseppe Penna,et al.  Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. , 2005, Blood.

[17]  M. Pauza,et al.  Islet-Specific Expression of CXCL10 Causes Spontaneous Islet Infiltration and Accelerates Diabetes Development1 , 2005, The Journal of Immunology.

[18]  Zhiliang Wang,et al.  Plasmacytoid Dendritic Cell Precursors Induce Allogeneic T‐Cell Hyporesponsiveness and Prolong Heart Graft Survival , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[19]  M. Clare-Salzler,et al.  Dexamethasone Induces IL‐10‐Producing Monocyte‐Derived Dendritic Cells with Durable Immaturity , 2005, Scandinavian journal of immunology.

[20]  V. Oliveira,et al.  IFN-γ production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo , 2005, The Journal of experimental medicine.

[21]  B. Kwon,et al.  Enhanced CD4 T Cell Responsiveness in the Absence of 4-1BB1 , 2005, The Journal of Immunology.

[22]  M. Roncarolo,et al.  Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. , 2005, Blood.

[23]  L. Adorini,et al.  Suppressive Effect of 1α,25-Dihydroxyvitamin D3 on Type I IFN-Mediated Monocyte Differentiation into Dendritic Cells: Impairment of Functional Activities and Chemotaxis1 , 2005, The Journal of Immunology.

[24]  C. Mathieu,et al.  1alpha,25-dihydroxyvitamin D3 or analogue treated dendritic cells modulate human autoreactive T cells via the selective induction of apoptosis. , 2004, Journal of autoimmunity.

[25]  Hye-young Park,et al.  4-1BB-mediated immunotherapy of rheumatoid arthritis , 2004, Nature Medicine.

[26]  G. Freeman,et al.  PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[27]  B. Roep,et al.  Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice , 2004, Diabetologia.

[28]  R. Offringa,et al.  Prolongation of skin graft survival by modulation of the alloimmune response with alternatively activated dendritic cells1 , 2003, Transplantation.

[29]  S. Ehlers,et al.  Role of tumour necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF , 2003, Annals of the rheumatic diseases.

[30]  M. Jordana,et al.  The B7 family member B7-H3 preferentially down-regulates T helper type 1–mediated immune responses , 2003, Nature Immunology.

[31]  G. Zhu,et al.  B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. , 2003, Immunity.

[32]  G. Firestein.  Evolving concepts of rheumatoid arthritis , 2003, Nature.

[33]  O. Majdic,et al.  B7-H1 (Programmed Death-1 Ligand) on Dendritic Cells Is Involved in the Induction and Maintenance of T Cell Anergy 1 , 2003, The Journal of Immunology.

[34]  Lieping Chen,et al.  Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease , 2002, Nature Medicine.

[35]  R. Kumar,et al.  Distinctive dendritic cell modulation by vitamin D(3) and glucocorticoid pathways. , 2002, Biochemical and biophysical research communications.

[36]  C. Mathieu,et al.  Redirection of human autoreactive T-cells Upon interaction with dendritic cells modulated by TX527, an analog of 1,25 dihydroxyvitamin D(3). , 2002, Diabetes.

[37]  David F. Richards,et al.  In Vitro Generation of Interleukin 10–producing Regulatory CD4+ T Cells Is Induced by Immunosuppressive Drugs and Inhibited by T Helper Type 1 (Th1)– and Th2-inducing Cytokines , 2002, The Journal of experimental medicine.

[38]  D. Fuchs,et al.  More rapid method for simultaneous measurement of tryptophan and kynurenine by HPLC. , 2002, Clinical chemistry.

[39]  Yuetsu Tanaka,et al.  Microbial Compounds Selectively Induce Th1 Cell-Promoting or Th2 Cell-Promoting Dendritic Cells In Vitro with Diverse Th Cell-Polarizing Signals1 , 2002, The Journal of Immunology.

[40]  H. Drexhage,et al.  1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes. , 2001, European journal of endocrinology.

[41]  M. Roncarolo,et al.  Type 1 T regulatory cells , 2001, Immunological reviews.

[42]  G. Freeman,et al.  PD-L2 is a second ligand for PD-1 and inhibits T cell activation , 2001, Nature Immunology.

[43]  A. Enk,et al.  Induction of Interleukin 10–Producing, Nonproliferating Cd4+ T Cells with Regulatory Properties by Repetitive Stimulation with Allogeneic Immature Human Dendritic Cells , 2000, The Journal of experimental medicine.

[44]  G. Freeman,et al.  Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation , 2000, The Journal of experimental medicine.

[45]  A. B. Lyons,et al.  Analysing cell division in vivo and in vitro using flow cytometric measurement of CFSE dye dilution. , 2000, Journal of immunological methods.

[46]  R. Offringa,et al.  Glucocorticoids transform CD40-triggering of dendritic cells into an alternative activation pathway resulting in antigen-presenting cells that secrete IL-10. , 2000, Blood.

[47]  P. Allavena,et al.  Vitamin D3 Affects Differentiation, Maturation, and Function of Human Monocyte-Derived Dendritic Cells1 , 2000, The Journal of Immunology.

[48]  R. Kumar,et al.  Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. , 2000, Biochemical and biophysical research communications.

[49]  J. D. de Fijter,et al.  The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells. , 2000, European journal of immunology.

[50]  L. Adorini,et al.  1α,25-Dihydroxyvitamin D3 Inhibits Differentiation, Maturation, Activation, and Survival of Dendritic Cells Leading to Impaired Alloreactive T Cell Activation , 2000, The Journal of Immunology.

[51]  P. Lipsky,et al.  Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial , 1999, The Lancet.

[52]  P. Kalinski,et al.  T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal. , 1999, Immunology today.

[53]  P. Kalinski,et al.  Prostaglandin E2 induces the final maturation of IL-12-deficient CD1a+CD83+ dendritic cells: the levels of IL-12 are determined during the final dendritic cell maturation and are resistant to further modulation. , 1998, Journal of immunology.

[54]  D. Munn,et al.  Prevention of allogeneic fetal rejection by tryptophan catabolism. , 1998, Science.

[55]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[56]  T. Tanimoto,et al.  Interferon‐γ‐inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin‐12 for interferon‐γ production , 1996 .

[57]  T. Tanimoto,et al.  Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production. , 1996, European journal of immunology.

[58]  J. Banchereau,et al.  Fas ligation induces apoptosis of CD40-activated human B lymphocytes , 1995, The Journal of experimental medicine.

[59]  H. Mcdevitt,et al.  Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-alpha and interleukin 1. , 1990, Proceedings of the National Academy of Sciences of the United States of America.