Defective CD 8 + CD 28 − regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy

Summary 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 CD 8 + CD 28 − regulatory T cells ( T reg ) contribution to the immunoregulatory network in health and in RA . In health, CD 8 + CD 28 − T reg are suppressive but, unlike CD 4 + T reg , they function predominantly through the action of soluble mediators such as interleukin ( IL )‐10 and transforming growth factor ( TGF )‐β. Neutralization of TGF‐ β consistently reduced CD 8 + C D28 − T reg suppressor function in vitro . RA , CD 8 + CD 28 − 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 ‐10 R . This expression was found to be restored following in‐vitro addition of a tumour necrosis factor inhibitor ( TNFi ). Deficiencies in both the CD 8 + CD 28 − T reg population and reduced sensitivity of the T responder cells impact upon their regulatory function in RA . TNFi therapy partially restores CD 8 + CD 28 − T reg ability in vivo and in vitro , despite the defects in expression of functionally relevant molecules by RA CD 8 + CD 28 − T reg compared to healthy controls. This study places CD 8 + CD 28 − T reg cells in the scheme of immune regulation alongside CD 4 + 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.