The transfer of maternal autoantibody (autoAb) to the progeny can cause neonatal autoimmune diseases. An example is the fatal congenital heart block elicited by maternal SSA/SSB antibodies in Sjogren’s patients. Disease mechanism is unknown but can now be investigated in a nAOD model developed in our laboratory. Ovarian inflammation and atrophy occurs in C57BL/6 Rag ko pups after the exposure to maternal autoAb against ovarian zona pellucida 3 within 1-5 days of life. Resistance to nAOD induction in both NK cell-depleted Rag ko pups, and Rag/common gamma chain (Rag/γc) double ko pups demonstrates the critical role of NK cells. Notably, neonatal but not adult NK cells restore nAOD in Rag/γc ko pups. Compared to adult NK cells, neonatal NK cells have lower expression of Ly49 receptors and higher frequency of the CD27+ subset. We now show that the expression of CD27, CXCR3 and IFNγ by neonatal NK cells are crucial for nAOD. Furthermore, Ly49C/I-depleted adult NK cells acquire the ability to induce nAOD. This suggests that the low expression of Ly49 reduces the activation threshold and enhances the pathogenic capacity of neonatal NK cells. Lastly, FcgRIII expression on both neonatal NK cells and ovarian resident macrophages and dendritic cells (APC) is obligatory for nAOD induction. However, ovarian APC requirement is not ontogenetically regulated. We conclude that the unique properties of neonatal NK cell predispose newborns to autoimmune disease by maternal autoAb.