CCR6 is expressed on an IL-10-producing, autoreactive memory T cell population with context-dependent regulatory function

J Exp Med. 2010 Mar 15;207(3):565-77. doi: 10.1084/jem.20091021. Epub 2010 Mar 1.

Abstract

Interleukin (IL)-10 produced by regulatory T cell subsets is important for the prevention of autoimmunity and immunopathology, but little is known about the phenotype and function of IL-10-producing memory T cells. Human CD4(+)CCR6(+) memory T cells contained comparable numbers of IL-17- and IL-10-producing cells, and CCR6 was induced under both Th17-promoting conditions and upon tolerogenic T cell priming with transforming growth factor (TGF)-beta. In normal human spleens, the majority of CCR6(+) memory T cells were in the close vicinity of CCR6(+) myeloid dendritic cells (mDCs), and strikingly, some of them were secreting IL-10 in situ. Furthermore, CCR6(+) memory T cells produced suppressive IL-10 but not IL-2 upon stimulation with autologous immature mDCs ex vivo, and secreted IL-10 efficiently in response to suboptimal T cell receptor (TCR) stimulation with anti-CD3 antibodies. However, optimal TCR stimulation of CCR6(+) T cells induced expression of IL-2, interferon-gamma, CCL20, and CD40L, and autoreactive CCR6(+) T cell lines responded to various recall antigens. Notably, we isolated autoreactive CCR6(+) T cell clones with context-dependent behavior that produced IL-10 with autologous mDCs alone, but that secreted IL-2 and proliferated upon stimulation with tetanus toxoid. We propose the novel concept that a population of memory T cells, which is fully equipped to participate in secondary immune responses upon recognition of a relevant recall antigen, contributes to the maintenance of tolerance under steady-state conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • Gene Expression Regulation
  • Homeostasis / immunology
  • Humans
  • Immunologic Memory*
  • Immunosuppression Therapy
  • Interferon-gamma / genetics
  • Interleukin-10 / biosynthesis
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, CCR6 / genetics*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / pharmacology

Substances

  • CCR6 protein, human
  • Interleukin-2
  • Receptors, Antigen, T-Cell
  • Receptors, CCR6
  • Transforming Growth Factor beta
  • Interleukin-10
  • Interferon-gamma