Beyond a single signal: How can bovine pregnancy be established without IFNT?

Interferon tau (IFNT) has been regarded as the dominant conceptus signal for maternal recognition of pregnancy (MRP) in ruminants. In cattle, IFNT is classically proposed to prevent luteolysis by suppressing uterine luteolytic pulses of prostaglandin F2α (PGF2α). IFNT also induces endometrial interferon-stimulated genes (ISGs) such as ISG15, MX dynamin-like GTPase 2 (MX2), and 2'-5'-oligoadenylate synthetase 1 (OAS1), thereby supporting uterine receptivity and an attachment-supportive immune milieu. A recent loss-of-function report using conceptuses lacking functional IFNT challenges this view by describing conceptus elongation and persistence of luteal function in a subset of recipients despite markedly reduced uterine ISG induction during the peri-implantation window. Here, we interpret this claim conservatively and specify experimental boundary conditions that currently limit generalization, including somatic cell nuclear transfer (SCNT), multi-embryo transfer, limited sample size, and the absence of direct physiological readouts of PGF2α pulsatility and the estrogen receptor 1 (ESR1) and oxytocin receptor (OXTR) axis. We then summarize possible buffering routes that could support early pregnancy when IFNT input is weakened, focusing on prostaglandin network rerouting toward luteoprotective outputs such as PGE2, extracellular vesicle (EV)-mediated communication, steroid-immune interactions, and corpus luteum (CL) gating of luteolytic sensitivity. Finally, we discuss how bovine endogenous retrovirus (BERV) long terminal repeats (LTRs) retaining interferon-responsive motifs, including interferon-stimulated response elements (ISREs), gamma-activated sequences (GAS), and ETS-family motifs, may act as enhancer substrates that amplify cytokine inputs in a cell-type and chromatin-dependent manner. Overall, we suggest that IFNT should be evaluated as a frequently dominant signal within a system that includes parallel buffering routes, such that the apparent requirement for IFNT can vary with conceptus load, uterine endocrine conditions, and ERV-derived regulatory architecture.