Treg und Th17-Zellen: Verwandtschaft mit Folgen

ZUSAMMENFASSUNG

Verschiedene Helfer-T-Zellen (Th) unterscheiden sich in Merkmalen und Funktionen. Th1 werden durch IL-12/IFN-gamma induziert, exprimieren T-bet und produzieren IFN-gamma. IL-17-produzierende Th17 exprimieren RORC, tragen den Chemokinrezeptor CCR6 und werden durch IL-1beta/IL-6/IL-23 stimuliert. Regulatorische T-Zellen (Treg) werden durch IL-2/TGF-beta stimuliert, exprimieren FoxP3 und produzieren IL-10. Th1 sind physiologischerweise an der intrazellulären Erregerabwehr beteiligt, Th2 von Parasiten, Th17 von extrazellulären Bakterien und Pilzen und Treg an der peripheren T-Zell-Homöostase. Eine Dysbalance zwischen Treg/Th1 und Th17 wird mit Autoimmunprozessen in Zusammenhang gebracht. Insbesondere synoviale Th1/Th17-Zellen, die CD161 exprimieren, zeigen enge Korrelationen mit schweren Verläufen der JIA, während IL-17-produzierende Treg/Th17-Zellen pro- und antiinflammatorische Fähigkeiten vereinen können. Alle Th weisen eine hohe Plastizität in unterschiedlichen inflammatorischen Milieus auf. Es gibt Hinweise, dass eine effiziente Hemmung von bestimmten Zytokinen zu einer Rekonstitution der Treg-Funktion beiträgt, was in neuen Therapieansätzen genutzt werden könnte.

SUMMARY

Different T helper cell types (Th) demonstrate different features and functions. Th1 are stimulated by IL-12/IFN-gamma, express T-bet and produce IFN-gamma. IL-17-producing Th17 express RORC, are positive for chemokine receptor CCR6 and are stimulated by IL-1beta/IL-6/IL-23. IL-2 and TGF-beta stimulate Treg, which express FoxP3 and produce IL-10. Physiologically, Th1 are directed against intracellular pathogens, whereas Th2 fend off parasites, and Th17 extracellular bacteria and fungi. Treg are involved in the peripheral T cell homeostasis. A dysbalance between Treg and Th1 as well as Th17 is critical in the pathogenesis of many T cell-mediated autoimmune disorders. Particularly, synovial Th1/Th17 cells expressing CD161 correlate with severe courses of JIA. IL-17-producing Treg/Th17 cells combine pro- and anti-inflammatory abilities. All Th subtypes demonstrate a high grade of plasticity in different inflammatory cytokine milieus. There is upcoming evidence, that efficient blockade of certain cytokines may contribute to the reconstitution of Treg function, which may be utilized in novel therapeutic approaches.

Schlüsselwörter

Th17 - Treg - Autoimmunarthritis - Plastizität

Keywords

Th17 - Treg - autoimmune arthritis - plasticity

• Literatur

• 1 Lin YT, Wang CT, Gershwin ME. et al The pathogenesis of oligoarticular/polyarticular vs systemic juvenile idiopathic arthritis. Autoimmun Rev 2011; 10: 482-489
• 2 Mahendra A, Misra R, Aggarwal A. Th1 and Th17 predominance in the enthesitis-related arthritis form of juvenile idiopathic arthritis. J Rheumatol 2009; 36: 1730-1706
• 3 Sakaguchi S, Miyara M, Costantino CM. et al FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010; 10: 490-500
• 4 Nistala K, Wedderburn LR. Th17 and regulatory T cells: rebalancing pro- and anti-inflammatory forces in autoimmune arthritis. Rheumatology (Oxford) 2009; 48: 602-606
• 5 Nistala K, Moncrieffe H, Newton KR. et al Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum 2008; 58: 875-887
• 6 Olivito B, Simonini G, Ciullini S. et al Th17 transcription factor RORC2 is inversely correlated with FOXP3 expressin in the joints of children with juvenile idiopathic arthritis. J Rheumatol 2009; 36: 2017-2024
• 7 Maggi L, Cosmi L, Simonini G. et al T cell subpopulations in juvenile idiopathic arthritis and their modifications after biotherapies. Autoimmun Rev 2016; 15: 1141-1144
• 8 Cosmi L, Cimaz R, Maggi L. et al Evidence of the transient nature of the Th17 phenotype of CD4+CD161+T cells in the synovial fluid of patients with patients with juvenile idiopathic arthritis. Arthritis Rheum 2011; 63: 2504-2515
• 9 Nistala K, Adams S, Cambrook H. et al Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A 2010; 107: 14751-14756
• 10 Maggi L, Cimaz R, Capone M. et al Brief report: etanercept inhibits the tumor necrosis factor α-driven shift of Th17 lymphocytes toward a nonclassic Th1 phenotype in juvenile idiopathic arthritis. Arthritis Rheumatol 2014; 66: 1372-1377
• 11 Mazzoni A, Santarlasci V, Maggi L. et al Demethylation of the RORC2 and IL17A in human CD4+T lymphocytes defines Th17 origin of nonclassic Th1 cells. J Immunol 2015; 194: 3116-3126
• 12 Foley C, Floudas A, Canavan M. et al Increased T cell plasticity with dysregulation of T follicular helper, T peripheral helper and T regulatory cell responses in children with JIA and Down syndrome-associated arthritis. Arthr Rheumatol 2019 https://doi.org/10.1002/art.41150
• 13 Annunziato F, Cosmi L, Liotta F. et al Main features of human T helper 17 cells. Ann N Y Acad Sci 2013; 1284: 66-70
• 14 Wehrens EJ, Mijnheer G, Duurland CL. et al Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells. Blood 2011; 118: 3538-3548
• 15 Haufe S, Haug M, Schepp C. et al Impaired suppression of synovial fluid CD4+CD25-T cells from patients with juvenile idiopathic arthritis by CD4+CD25+ Treg cells. Arthritis Rheum 2011; 63: 3153-3162
• 16 Almanzar G, Klein M, Schmalzing M. et al Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis. Int Arch Allergy Immunol 2016; 171: 141-154
• 17 Ugur E, Simon D, Almanzar G. et al Increased proportions of functionally impaired regulatory T cell subsets in systemic sclerosis. Clin Immunol 2017; 184: 54-62
• 18 Kleinewietfield M, Hafler DA. Plasticity of human Treg and Th17 cells. Sem Immunol 2013; 25: 305-312
• 19 Ehrenstein MR, Evans JG, Singh A. et al Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med 2004; 200: 277-285
• 20 McGovern JL, Nguyen DX, Notley CA. et al Th 17 cells are restrained by Treg cells via the inhibition of interleukin-6 in patients with rheumatoid arthritis responding to anti-tumor necrosis factor antibody therapy. Arthritis Rheum 2012; 64: 3129-138
• 21 Nadkarni S, Mauri C, Ehrenstein MR. Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med 2007; 204: 33-39
• 22 Bystrom J, Clanchy FI, Taher TE. et al TNFα in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune inflammatory diseases. Cytokine 2018; 101: 4-13
• 23 Kim EY, Moudgil KD. Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines. Cytokine 2017; 98: 87-96
• 24 Komatsu N, Takayanagi H. Regulatory T cells in arthritis. Prog Mol Biol Transl Sci 2015; 136: 207-215