Development of Th1-Inducing Capacity in Myeloid Dendritic Cells Requires Environmental Instruction1

Dendritic cells (DC) are key initiators of primary immune responses. Myeloid DC can secrete IL-12, a potent Th1-driving factor, and are often viewed as Th1-promoting APC. Here we show that neither a Th1- nor a Th2-inducing function is an intrinsic attribute of human myeloid DC, but both depend on environmental instruction. Uncommitted immature DC require exposure to IFN-γ, at the moment of induction of their maturation or shortly thereafter, to develop the capacity to produce high levels of IL-12p70 upon subsequent contact with naive Th cells. This effect is specific for IFN-γ and is not shared by other IL-12-inducing factors. Type 1-polarized effector DC, matured in the presence of IFN-γ, induce Th1 responses, in contrast to type 2-polarized DC matured in the presence of PGE2 that induce Th2 responses. Type 1-polarized effector DC are resistant to further modulation, which may facilitate their potential use in immunotherapy.

[1]  A. O’Garra,et al.  Cytokines induce the development of functionally heterogeneous T helper cell subsets. , 1998, Immunity.

[2]  L. Fabbri,et al.  Beta2-agonists prevent Th1 development by selective inhibition of interleukin 12. , 1997, The Journal of clinical investigation.

[3]  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.

[4]  B. Pulendran,et al.  Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[5]  B. Fazekas de St. Groth,et al.  The evolution of self-tolerance: a new cell arises to meet the challenge of self-reactivity. , 1998, Immunology today.

[6]  H. Weiner,et al.  Induction of Th2 cell differentiation in the primary immune response: dendritic cells isolated from adherent cell culture treated with IL-10 prime naive CD4+ T cells to secrete IL-4. , 1998, International immunology.

[7]  R. Vabulas,et al.  Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells , 1998, European journal of immunology.

[8]  T. Mosmann,et al.  The expanding universe of T-cell subsets: Th1, Th2 and more. , 1996, Immunology today.

[9]  V. Verhasselt,et al.  Inhibition of human dendritic cell functions by methylprednisolone. , 1999, Transplantation.

[10]  N. Romani,et al.  High Level IL-12 Product ion by Murine Dendrit ic Cells : Upregulation via MHC Class II and CD 40 Molecules and Downregulat ion by IL-4 and IL-10 By , 2003 .

[11]  C. Biron.  Activation and function of natural killer cell responses during viral infections. , 1997, Current opinion in immunology.

[12]  A. Enk,et al.  Induction of tolerance by IL-10-treated dendritic cells. , 1997, Journal of immunology.

[13]  P. Kalinski,et al.  Glucocorticoids inhibit bioactive IL-12p70 production by in vitro-generated human dendritic cells without affecting their T cell stimulatory potential. , 1998, Journal of immunology.

[14]  P. Kalinski,et al.  Final maturation of dendritic cells is associated with impaired responsiveness to IFN-gamma and to bacterial IL-12 inducers: decreased ability of mature dendritic cells to produce IL-12 during the interaction with Th cells. , 1999, Journal of immunology.

[15]  N. Kadowaki,et al.  Reciprocal control of T helper cell and dendritic cell differentiation. , 1999, Science.

[16]  K. Toellner,et al.  T Helper 1 (th1) and Th2 Characteristics Start to Develop during T Cell Priming and Are Associated with an Immediate Ability to Induce Immunoglobulin Class Switching , 1998 .

[17]  A. Iwasaki,et al.  Freshly Isolated Peyer's Patch, but Not Spleen, Dendritic Cells Produce Interleukin 10 and Induce the Differentiation of T Helper Type 2 Cells , 1999, The Journal of experimental medicine.

[18]  V. Verhasselt,et al.  Bacterial lipopolysaccharide stimulates the production of cytokines and the expression of costimulatory molecules by human peripheral blood dendritic cells: evidence for a soluble CD14-dependent pathway. , 1997, Journal of immunology.

[19]  Hanno Langen,et al.  Maturation, Activation, and Protection of Dendritic Cells Induced by Double-stranded RNA , 1999, The Journal of experimental medicine.

[20]  J. Mcghee,et al.  Dendritic cells from different tissues induce production of different T cell cytokine profiles , 1996, Journal of leukocyte biology.

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

[22]  R. Leurs,et al.  Histamine inhibits the production of interleukin-12 through interaction with H2 receptors. , 1998, The Journal of clinical investigation.

[23]  X. Mo,et al.  Matching antibody class with pathogen type and portal of entry: cognate mechanisms regulate local isotype expression patterns in lymph nodes draining the respiratory tract of mice inoculated with respiratory viruses, according to virus replication competence and site of inoculation. , 1997, Journal of immunology.

[24]  P. Matzinger.  Tolerance, danger, and the extended family. , 1994, Annual review of immunology.

[25]  N. Williams,et al.  The role of small intestinal antigen‐presenting cells in the induction of T‐cell reactivity to soluble protein antigens: association between aberrant presentation in the lamina propria and oral tolerance , 1996, Immunology.

[26]  P. Kalinski,et al.  High-level IL-12 production by human dendritic cells requires two signals. , 1998, International immunology.

[27]  M. de Boer,et al.  Human dendritic cells require exogenous interleukin-12-inducing factors to direct the development of naive T-helper cells toward the Th1 phenotype. , 1997, Blood.

[28]  A. Lanzavecchia,et al.  Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation , 1996, The Journal of experimental medicine.

[29]  M. Moser,et al.  Effect of interleukin‐10 on dendritic cell maturation and function , 1997, European journal of immunology.

[30]  R. Steinman,et al.  The dendritic cell system and its role in immunogenicity. , 1991, Annual review of immunology.

[31]  Kenneth M. Murphy,et al.  Dendritic cells and macrophages are required for Th1 development of CD4+ T cells from αβ TCR transgenic mice: IL-12 substitution for macrophages to stimulate IFN-γ production is IFN-γ-dependent , 1993 .

[32]  R. Maldonado-López,et al.  CD8α+ and CD8α− Subclasses of Dendritic Cells Direct the Development of Distinct T Helper Cells In Vivo , 1999, The Journal of experimental medicine.