A study of RA patients refractory to anti-TNF-α therapy found that highly differentiated antigen epitope (AE)-specific CD8+ Teff cells were completely uninhibited by Tregs due to a mechanism that may be the result of AE-CD8+ Teff cells expressing an effector cell phenotype and gene profile and killing Treg cells in an NKG2D-dependent manner in vitro after antigen-specific activation [68]. Here, TNF is linked to rheumatoid arthritis.