Generation of Human CD8 T Regulatory Cells by CD40 Ligand–activated Plasmacytoid Dendritic Cells

Although CD8 T cell–mediated immunosuppression has been a well-known phenomenon during the last three decades, the nature of primary CD8 T suppressor cells and the mechanism underlying their generation remain enigmatic. We demonstrated that naive CD8 T cells primed with allogeneic CD40 ligand–activated plasmacytoid dendritic cells (DC)2 differentiated into CD8 T cells that displayed poor secondary proliferative and cytolytic responses. By contrast, naive CD8 T cells primed with allogeneic CD40 ligand–activated monocyte-derived DCs (DC1) differentiated into CD8 T cells, which proliferated to secondary stimulation and killed allogeneic target cells. Unlike DC1-primed CD8 T cells that produced large amounts of interferon (IFN)-γ upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-γ, and no IL-4, IL-5, nor transforming growth factor (TGF)-β. The addition of anti–IL-10–neutralizing monoclonal antibodies during DC2 and CD8 T cell coculture, completely blocked the generation of IL-10–producing anergic CD8 T cells. IL-10–producing CD8 T cells strongly inhibit the allospecific proliferation of naive CD8 T cells to monocytes, and mature and immature DCs. This inhibition was mediated by IL-10, but not by TGF-β. IL-10–producing CD8 T cells could inhibit the bystander proliferation of naive CD8 T cells, provided that they were restimulated nearby to produce IL-10. IL-10–producing CD8 T cells could not inhibit the proliferation of DC1-preactivated effector T cells. This study demonstrates that IL-10–producing CD8 T cells are regulatory T cells, which provides a cellular basis for the phenomenon of CD8 T cell–mediated immunosuppression and suggests a role for plasmacytoid DC2 in immunological tolerance.

[1]  Nina Bhardwaj,et al.  Antigen-Specific Inhibition of Effector T Cell Function in Humans after Injection of Immature Dendritic Cells , 2001, The Journal of experimental medicine.

[2]  F. Sallusto,et al.  Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells , 2000, Nature Immunology.

[3]  Kenneth M. Murphy,et al.  Dendritic cell regulation of TH1-TH2 development , 2000, Nature Immunology.

[4]  M. Salmon,et al.  Loss of CD28 expression on CD8(+) T cells is induced by IL-2 receptor gamma chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis. , 2000, International immunology.

[5]  S. Heimfeld,et al.  Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. , 2000, Blood.

[6]  K. Shortman Dendritic cells: Multiple subtypes, multiple origins, multiple functions , 2000 .

[7]  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.

[8]  A. Sher,et al.  Paralysis of dendritic cell IL-12 production by microbial products prevents infection-induced immunopathology. , 1999, Immunity.

[9]  S. Lederman,et al.  Inhibition of CD40 signaling pathway in antigen presenting cells by T suppressor cells. , 1999, Human immunology.

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

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

[12]  M. Rep,et al.  Phenotypic and Functional Separation of Memory and Effector Human CD8+ T Cells , 1997, The Journal of experimental medicine.

[13]  Hervé Groux,et al.  A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis , 1997, Nature.

[14]  J. Banchereau,et al.  The Enigmatic Plasmacytoid T Cells Develop into Dendritic Cells with Interleukin (IL)-3 and CD40-Ligand , 1997, The Journal of experimental medicine.

[15]  M. Klein,et al.  Phenotypic and functional separation of memory and effector human CD 8 + T cells , 1997 .

[16]  J. D. de Vries,et al.  Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells , 1996, The Journal of experimental medicine.

[17]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[18]  L. Chess,et al.  Murine CD8+ T cells that specifically delete autologous CD4+ T cells expressing V beta 8 TCR: a role of the Qa-1 molecule. , 1995, Immunity.

[19]  R. Coffman,et al.  Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. , 1994, Immunity.

[20]  H. Weiner,et al.  Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. , 1994, Science.

[21]  D. Mason,et al.  Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential , 1993, The Journal of experimental medicine.

[22]  A. Gaur,et al.  Requirement for CD8+ cells in T cell receptor peptide-induced clonal unresponsiveness. , 1993, Science.

[23]  T. Inoue,et al.  Establishment of stable CD8+ suppressor T cell clones and the analysis of their suppressive function. , 1992, Journal of immunological methods.

[24]  T. Mak,et al.  Less Mortality but More Relapses in Experimental Allergic Encephalomyelitis in CD8-/- Mice , 1992, Science.

[25]  B. Diamond,et al.  Revisiting and revising suppressor T cells. , 1992, Immunology today.

[26]  V. Kuchroo,et al.  Suppressor T cells: some answers but more questions. , 1992, Immunology today.

[27]  J. Banchereau,et al.  Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. , 1991, Science.

[28]  Y. Asano,et al.  CD8+ suppressor T cell clone capable of inhibiting the antigen- and anti-T cell receptor-induced proliferation of Th clones without cytolytic activity. , 1990, Journal of immunology.

[29]  E. Engleman,et al.  Differences in surface phenotype and mechanism of action between alloantigen-specific CD8+ cytotoxic and suppressor T cell clones. , 1990, Journal of immunology.

[30]  B. Bloom,et al.  On the mechanism of human T cell suppression. , 1989, International immunology.

[31]  E. Simpson Suppression of the immune response by cytotoxic T cells , 1988, Nature.

[32]  A. Lanzavecchia,et al.  T cells can present antigens such as HIV gp120 targeted to their own surface molecules , 1988, Nature.

[33]  G. Möller Do Suppressor T Cells Exist? , 1988, Scandinavian journal of immunology.

[34]  I. Cohen,et al.  Anti-idiotypic network induced by T cell vaccination against experimental autoimmune encephalomyelitis. , 1988, Science.

[35]  B. Benacerraf,et al.  Suppressor cells and immunoregulation. , 1984, Annual review of immunology.

[36]  D. Green,et al.  Immunoregulatory T-cell pathways. , 1983, Annual review of immunology.

[37]  P. Kilshaw,et al.  Suppressor T cells in mice made unresponsive to skin allografts , 1975, Nature.

[38]  R. Gershon,et al.  Cell interactions in the induction of tolerance: the role of thymic lymphocytes. , 1970, Immunology.