CD4 + regulatory and naïve T cells specific for factor VIII stand vis‐à‐vis to balance the immune response in healthy individuals

Additionally, inhibitory antibodies to FVIII rarely occur in healthy individuals resulting in acquired HA. [...]very few healthy individuals (0.2–1.0 per one million) [ 2], as well as one-third of HA patients, mount an aggressive auto- or alloimmune response to FVIII. Following stimulation of peripheral blood mononuclear cells (PBMCs) isolated from buffy coats of healthy individuals with full-length FVIII (rFVIII), the fusion protein (rFVIIIFc) and MOG for 16 h, the proportion of samples responding to the stimuli based on surface expression of CD154 (non-Treg) or CD137 (Treg) was compared. Both, rFVIII and rFVIIIFc stimulation (median of 68.4%) showed a higher proportion of activated naive T cells compared to the unstimulated control (median of 57.4%) (p < 0.001 and p = 0.002). [...]in this setting naive CD4+ T cells showed higher responsiveness towards either rFVIII product. Concerning reactivity towards FVIII, our data suggest that a significant proportion of healthy individuals possesses FVIII-specific T cells and that specific Tregs are produced during early tolerance development to bridle this cell population. [...]situations in which Treg functions are impaired might result in the formation of robust FVIII-specific T-cell responses eventually leading to the formation of FVIII-specific antibodies.