Defective CD8(+)CD28(-) regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy

S. Ceeraz, C. Hall, E. H. Choy, J. Spencer, V. M. Corrigall*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)


Balanced immunoregulatory networks are essential for maintenance of systemic tolerance. Disturbances in the homeostatic equilibrium between inflammatory mediators, immune regulators and immune effector cells are implicated directly in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). In this study we characterize the peripheral blood CD8(+)CD28(-) regulatory T cells (T-reg) contribution to the immunoregulatory network in health and in RA. In health, CD8(+)CD28(-) T-reg are suppressive but, unlike CD4(+)T(reg), they function predominantly through the action of soluble mediators such as interleukin (IL)-10 and transforming growth factor (TGF)-. Neutralization of TGF- consistently reduced CD8(+)CD28(-) T-reg suppressor function in vitro. RA, CD8(+)CD28(-) T-reg are increased numerically, but have reduced expression of inducible co-stimulator (ICOS) and programmed death 1 (PD-1) compared to healthy or disease controls. They produce more IL-10 but autologous T cells express less IL-10R. This expression was found to be restored following in-vitro addition of a tumour necrosis factor inhibitor (TNFi). Deficiencies in both the CD8(+)CD28(-) T-reg population and reduced sensitivity of the T responder cells impact upon their regulatory function in RA. TNFi therapy partially restores CD8(+)CD28(-) T-reg ability in vivo and in vitro, despite the defects in expression of functionally relevant molecules by RA CD8(+)CD28(-) T-reg compared to healthy controls. This study places CD8(+)CD28(-) T-reg cells in the scheme of immune regulation alongside CD4(+) T-reg cells, and highlights the importance of understanding impaired responsiveness to regulation that is common to these suppressor subsets and their restored function in response to TNFi therapy.

Original languageEnglish
Article numberN/A
Pages (from-to)18-26
Number of pages9
JournalClinical and Experimental Immunology
Issue number1
Publication statusPublished - Oct 2013


  • anti-TNF therapy
  • CD8(+) T cells
  • immunotherapy
  • regulatory T cells
  • rheumatoid arthritis


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