To elucidate the mechanisms that facilitate tolerance at the maternal-fetal interface, we are investigating the role of genes that are involved in peripheral self-tolerance in couples with idiopathic recurrent miscarriage. CTLA-4 is a negative regulator of T-cell proliferation and has been associated with human autoimmune disease. An AT(n) polymorphism in the 3'-untranslated region (UTR) of the human gene results in AT stretches that vary in length from 16 to 46 bp. We hypothesized that long stretches of AT repeats would result in mRNA instability, and reduced fetal survival in humans. We examined the transmission of AT(n) alleles in 60 couples with a history of > or = 3 unexplained spontaneous abortions to their 51liveborn children and 10 abortuses. The shorter allele was transmitted from heterozygous mothers to 26 of 35 liveborn children (chi2 = 8.3, P = 0.0040) and to three of nine aborted fetuses (chi2 = 1.0, P = 0.317). The shorter allele was transmitted from heterozygous fathers to 15 of 32 liveborn children (chi2 =0.12, P=0.726) and to five of eight aborted fetuses (chi2 = 0.5, P = 0.480). Furthermore, liveborn fetuses who inherited smaller alleles were more likely to represent the first successful pregnancy than liveborn fetuses who inherited larger maternal alleles (Pexact = 0.044) and fetuses of first pregnancies that inherited the smaller allele were significantly more likely to survive to term (Pexact = 0.0086). The preferential transmission of maternally-inherited shorter alleles to liveborn children, but random transmission of paternally-inherited alleles, suggests that CTLA-4 may be imprinted in humans and that this gene may play a role in inducing or maintaining tolerance at the maternal-fetal interface.