The role of retinoic acid-related orphan receptor variant 2 and IL-17 in the development and function of human CD4+ T cells

Eur J Immunol. 2009 Jun;39(6):1480-93. doi: 10.1002/eji.200838908.

Abstract

Th17 cells are defined by their capacity to produce IL-17, and are important mediators of inflammation and autoimmunity. Human Th17 cells express high levels of the retinoic acid-related orphan receptor variant 2 (RORC2), but it is currently unclear whether expression of this transcription factor alone is sufficient to recapitulate all the known properties of Th17 cells. We used lentivirus-mediated transduction to investigate the role of RORC2 in defining aspects of the human Th17 cell lineage. Expression of RORC2 induced production of IL-17A, IL-22, IL-6 and TNF-alpha, a Th17-cell-associated chemokine receptor profile and upregulation of CD161. RORC2-transduced T cells were hypo-responsive to TCR-mediated stimulation, a property shared with ex vivo Th17 cells and overcome by addition of exogenous IL-2 or IL-15. Co-culture experiments revealed that RORC2-expressing cells were partially resistant to Treg cells since production of IL-17 and proliferation were not suppressed. Evidence that IL-17 stimulates CD4(+) T cells to produce IL-2 and proliferate suggested that the resistance of Th17 cells to Treg-mediated suppression may be partly attributed to IL-17 itself. These findings demonstrate that expression of RORC2 in T cells has functional consequences beyond altering cytokine production and provides insight into the factors regulating the development of human Th17 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD28 Antigens / immunology
  • CD3 Complex / immunology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation / immunology*
  • Cell Lineage / immunology
  • Cell Proliferation / drug effects
  • Cytokines / metabolism
  • Cytokines / pharmacology
  • Gene Expression / genetics
  • Gene Expression Regulation / immunology
  • Genetic Vectors / genetics
  • Granzymes / metabolism
  • Humans
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism*
  • Interleukin-17 / pharmacology
  • Lentivirus / genetics
  • Lymphocyte Activation / immunology
  • NK Cell Lectin-Like Receptor Subfamily B / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Chemokine / metabolism
  • Receptors, Retinoic Acid / metabolism*
  • Receptors, Thyroid Hormone / metabolism*
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • Transduction, Genetic

Substances

  • CD28 Antigens
  • CD3 Complex
  • Cytokines
  • Interleukin-17
  • NK Cell Lectin-Like Receptor Subfamily B
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Receptors, Chemokine
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • Granzymes