Rheumatoid arthritis (RA) involves alterations in cytotoxic lymphoid differentiation, yet the precise phenotypic remodeling of circulating helper T cells and natural killer (NK) cells remains incompletely understood. We evaluated circulating CD4⁺CD28⁺ and CD4⁺CD28⁻ T-cell subsets and NKG2A⁺CD56⁺ NK cells, alongside granule-mediated cytotoxic markers (granzyme B and perforin) and the surface-bound death receptor Fas ligand (FasL), in 28 female patients with RA and 12 age-matched healthy female controls using multiparameter flow cytometry. CD4⁺CD28⁻ cells were increased in RA compared with controls (16.6% versus 6.5% of CD4⁺ cells). Within CD4⁺CD28⁻ cells, granzyme B positivity was markedly lower in RA (5.0% versus 62.0%), whereas FasL expression was higher (40.3% versus 22.5%). RA patients also exhibited a higher proportion of circulating NKG2A⁺CD56⁺ NK cells (6.1% versus 2.7% of PBMCs) with substantially lower granzyme B expression (8.4% versus 55.6%). Higher disease activity (DAS28-CRP) correlated positively with total NKG2A⁺CD56⁺ NK cell frequencies and intracellular perforin expression in both CD4⁺CD28⁺ T cells and NKG2A⁺CD56⁺ NK cells, as well as lower FasL expression in CD4⁺CD28⁻ cells. These findings support a disease-associated phenotypic remodeling of circulating cytotoxic markers in RA, characterized by shifted granzyme B and FasL expressions in CD4⁺CD28⁻ T cells and NKG2A⁺CD56⁺ NK cells, although whether these profiles translate into altered cytotoxic kinetics remains to be functionally determined.

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