High antigen dose and activated dendritic cells enable Th cells to escape regulatory T cell-mediated suppression in vitro

被引:73
作者
Georger, TC
Bilsborough, J
Viney, JL
Norment, AM
机构
[1] Amgen Corp, Dept Immune Regulat, Seattle, WA 98101 USA
[2] Amgen Corp, Dept Autoimmun & Inflammat, Seattle, WA 98101 USA
关键词
B cell; dendritic cell; DO11.10; TCR; regulatory T cell; CD4(+)CD25(+);
D O I
10.1002/immu.200310026
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
CD4(+)CD25(+) regulatory T cells (Tregs) are critical for peripheral tolerance and prevention of autoimmunity. In vitro coculture studies have revealed that increased costimulation breaks Treg-mediated suppression in response to anti-CD3 or antigen. However, it was unclear whether loss of suppression arose from inactivation of Tregs or whether increased stimulation caused Th cells to escape suppression. We have investigated conditions that allow or override Treg-mediated suppression using DO11.10 TCR-transgenic T cells and chicken ovalbumin peptide 323-339-pulsed antigen-presenting cells. Treg suppression of Th proliferation is broken with potent stimulation, using activated spleen cells and high antigen dose, but is intact at low antigen dose. Costimulation with CD80 and CD86 expressed on activated dendritic cells was essential for Th cell escape from suppression at a high antigen dose. Potently stimulated Tregs were functional since they reduced levels of IL-2, IFN-gamma, IL-4 and Th CD25 expression in cocultures. Furthermore, Tregs responding to high antigen dose and activated splenocytes retained the ability to suppress proliferation, but only of Th cells responding to a sub-optimal dose of independent antigen. Together, our results demonstrate that under conditions of strong antigen-specific stimulation, Tregs remain functional, but Th cells escape Treg-mediated suppression.
引用
收藏
页码:502 / 511
页数:10
相关论文
共 34 条
  • [1] Mouse type IIFN-producing cells are immature APCs with plasmacytoid morphology
    Asselin-Paturel, C
    Boonstra, A
    Dalod, M
    Durand, I
    Yessaad, N
    Dezutter-Dambuyant, C
    Vicari, A
    O'Garra, A
    Biron, C
    Brière, F
    Trinchieri, G
    [J]. NATURE IMMUNOLOGY, 2001, 2 (12) : 1144 - 1150
  • [2] Immunobiology of dendritic cells
    Banchereau, J
    Briere, F
    Caux, C
    Davoust, J
    Lebecque, S
    Liu, YT
    Pulendran, B
    Palucka, K
    [J]. ANNUAL REVIEW OF IMMUNOLOGY, 2000, 18 : 767 - +
  • [3] Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4+25+ immunoregulatory T cells
    Bensinger, SJ
    Bandeira, A
    Jordan, MS
    Caton, AJ
    Laufer, TM
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2001, 194 (04) : 427 - 438
  • [4] Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colony-stimulating factor-treated mice
    Björck, P
    [J]. BLOOD, 2001, 98 (13) : 3520 - 3526
  • [5] Cederbom L, 2000, EUR J IMMUNOL, V30, P1538, DOI 10.1002/1521-4141(200006)30:6<1538::AID-IMMU1538>3.0.CO
  • [6] 2-X
  • [7] Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo
    Gavin, MA
    Clarke, SR
    Negrou, E
    Gallegos, A
    Rudensky, A
    [J]. NATURE IMMUNOLOGY, 2002, 3 (01) : 33 - 41
  • [8] Itoh M, 1999, J IMMUNOL, V162, P5317
  • [9] Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells
    Jonuleit, H
    Schmitt, E
    Schuler, G
    Knop, J
    Enk, AH
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2000, 192 (09) : 1213 - 1222
  • [10] Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide
    Jordan, MS
    Boesteanu, A
    Reed, AJ
    Petrone, AL
    Holenbeck, AE
    Lerman, MA
    Naji, A
    Caton, AJ
    [J]. NATURE IMMUNOLOGY, 2001, 2 (04) : 301 - 306