T cell receptors consist either of an α-chain combined with a β-chain or a γ-chain combined with a δ-chain. αβ T cells constitute the majority of T cells in human blood throughout life. Flow cytometric analyses presented in this study, which focus on the representation of the developmental (naive and memory) subsets of γδ T cells, show by function and phenotype that this lineage contains both naive and memory cells. In addition, we show that the representation of naive T cells is higher among αβ than γδ T cells in adults and that the low frequency of naive γδ T cells in adults reflects ontological differences between the two major γδ subsets, which are distinguished by expression of Vδ1 vs Vδ2 δ-chains. Vδ1 cells, which mirror αβ cells with respect to naive representation, predominate during fetal and early life, but represent the minority of γδ cells in healthy adults. In contrast, Vδ2 cells, which constitute the majority of adult γδ cells, show lower frequencies of naive cells than Vδ1 early in life and show vanishingly small naive frequencies in adults. In essence, nearly all naive Vδ2 cells disappear from blood by 1 year of life. Importantly, even in children less than 1 year old, most of the nonnaive Vδ2 cells stain for perforin and produce IFN-γ after short-term in vitro stimulation. This represents the earliest immunological maturation of any lymphocyte compartment in humans and most likely indicates the importance of these cells in controlling pathology due to common environmental challenges.

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Preclinical Research Although acetaminophen (APAP) is an effective analgesic and anti-pyretic, APAP overdose is the most frequent cause of serious, often lethal, drug-induced hepatotoxicity. Administration of N-acetyl cysteine (NAC) within 8 hours of APAP overdose effectively mitigates APAP-induced hepatotoxicity. Thus, preventing APAP toxicity before it occurs by formulating APAP with NAC is logical and, as we show here in a mouse model, is effective in preventing APAP toxicity. Thus, toxic oral APAP doses sufficient to cause severe widespread liver damage do not cause significant damage when administered concurrently with equal amounts of NAC, that is, in the NAC-APAP treated animals, hepatic transaminases increase only marginally and liver architecture remains fully intact. Thus, we conclude that concomitant oral dosing with APAP and NAC can provide a convenient and effective way of preventing toxicity associated with large dosage of APAP. From a public health perspective, these findings support the concept that a co-formulation of APAP plus NAC is a viable over-the-counter (OTC) alternative to the current practice of providing APAP OTC and treating APAP toxicity if/when it occurs. In essence, our findings indicate that replacing the current OTC APAP with a safe and functional APAP/NAC formulation could prevent the accidental and intentional APAP toxicity that occurs today.

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