Review Article

New complexities in helper T cell fate determination and the implications for autoimmune diseases

Authors

Hiroaki Takatori¹, Yuka Kanno¹, Zhi Chen^1,2 and John J. O’Shea¹

1. Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Room 13C120, 10 Center Drive, MSC-1930, Bethesda, MD 20892, USA
2. Present address: Faculty of Medicine, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland

Received:

22 February 2008

Accepted:

1 June 2008

Published online:

5 August 2008

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Abstract

This review examines evidence that rheumatoid arthritis (RA) depends on autoimmunity to articular collagen, and mechanisms whereby autoantibodies to type II collagen contribute to disease development. Three major autoantigenic reactants have been identified in RA; the corresponding autoantibodies are rheumatoid factor (RF), antibodies to citrullinated peptide antigens (ACPA), citrullinated peptides (anti-CCP), and anti-type II collageRecently, new complexities in cell fate decision for helper T cells have emerged. One new lineage, which has come to be called Th17 cells, selectively produces proinflammatory cytokines including interleukin-17 (IL-17, A and F), IL-21, and IL-22. In conjunction with transforming growth factor β-1 (TGFβ-1), IL-6, IL-21, and IL-23, which activate the transcription factor, signal transducer, and activator of transcription 3 (Stat3), the expression of another transcription factor, retinoic acid-related orphan receptor-γt (RORγt) leads to the differentiation of Th17 cells in mice. Other cytokines including IL-2, IL-4, interferon-γ (IFN-γ), and IL-27 inhibit Th17 differentiation. However, IL-2 acting with TGFβ-1 induces differentiation of naive CD4⁺ T cells to become regulatory T cells (Tregs). Th17 cells are now known to play an important role not only in the pathogenesis of inflammation and autoimmune diseases, but also host defense against extracellular bacteria. Conversely, extensive data substantiate the role of Tregs as essential in maintenance of peripheral tolerance. Selectively targeting Tregs and Th17 cells are likely to be important strategies in the treatment of inflammatory and autoimmune diseases in humans.

Key words

Th17 cells - Autoimmune diseases - Inflammation - IL-17 - Rheumatoid arthritis