The hormone estrogen is involved in both female and male reproduction, as well as numerous other biological systems including the neuroendocrine, vascular, skeletal, and immune systems. Therefore, it is also implicated in many different diseases and conditions such as infertility, obesity, osteoporosis, endometriosis, and a variety of cancers. Estrogen works through its two distinct nuclear receptors, Estrogen Receptor alpha (ERα) and Estrogen Receptor beta (ERβ). Various transcriptional regulation mechanisms have been identified as the mode of action for estrogen, mainly the classical mechanism with direct DNA binding but also a non-genomic mode of action and one using tethered or indirect binding. The expression profiles of ERα and ERβ are unique with the primary sites of ERα expression being the uterus and pituitary gland and the main site of ERβ expression being the granulosa cells of the ovary. Mouse models with knockout or mutation of Esr1 and Esr2 have furthered our understanding of the role each individual receptor plays in physiology. From these studies, it is known that the primary roles for ERα are in the uterus and neuroendocrine system, as female mice lacking ERα are infertile due to impaired ovarian and uterine function, whereas female mice lacking ERβ are subfertile due to ovarian defects. The development of effective therapies for estrogen-related diseases has relied on an understanding of the physiological roles and mechanistic functionalities of ERα and ERβ in various human health and disease.

The estrogen receptor (ER) is a ligand-dependent transcription factor containing two transcriptional activation domains. AF-1 is in the N terminus of the receptor protein and AF-2 activity is dependent on helix 12 of the C-terminal ligand-binding domain. Two point mutations of leucines 543 and 544 to alanines (L543A, L544A) in helix 12 minimized estrogen-dependent transcriptional activation and reversed the activity of the estrogen antagonists ICI182780 (ICI) and tamoxifen (TAM) into agonists in a similar manner that TAM activated WT ERα through AF-1 activation. To evaluate the physiological role of AF-1 and AF-2 for the tissueselective function of TAM, we generated an AF-2-mutated ERα knock-in (AF2ERKI) mouse model. AF2ERKI homozygote female mice have hypoplastic uterine tissue and rudimentary mammary glands similar to ERα-KO mice. Female mice were infertile as a result of anovulation from hemorrhagic cystic ovaries and elevated serum LH and E2 levels, although the mutant ERα protein is expressed in the AF2ERKI model. The AF2ERKI phenotype suggests that AF-1 is not activated independently, even with high serum E2 levels. ICI and TAM induced uterotropic and ER-mediated gene responses in ovariectomized AF2ERKI female mice in the same manner as in TAM-and E2-treated WT mice. In contrast, ICI and TAM did not act as agonists to regulate negative feedback of serum LH or stimulate pituitary prolactin gene expression in a different manner than TAM-or E2-treated WT mice. The functionality of the mutant ERα in the pituitary appears to be different from that in the uterus, indicating that ERα uses AF-1 differently in the uterus and the pituitary for TAM action.

Acknowledgement of the breadth of T-cell pleiotropy has provoked increasing interest in the degree to which functional responsiveness is elicited by environmental cues versus differentiation. This is particularly relevant for young animals requiring rapid responses to acute environmental exposure. In young mice, cd T cells are disproportionately important for immuno-protection. To examine the situation in humans, we compared populations and clones of T cells from term and preterm babies, and adults. By comparison with ab T cells, neonate-derived cd cells show stronger, pleiotropic functional responsiveness, and lack signatory deficits in IFN-c production. Emphasising the acquisition of functional competence in utero, IFN-c was produced by cd cells sampled from premature births, and, although one month's post-partum environmental exposure invariably increased their TNF-a production, it had no consistent effect on IFN-c or IL-2. In sum, cd cells seem well positioned at birth to contribute to immuno-protection and immuno-regulation, possibly compensating for selective immaturity in the ab compartment. With regard to the susceptibilities of preterm babies to viral infection, cd cells from preterm neonates were commonly impaired in Toll-like receptor-3 and -7 expression and compared with cells from term babies failed to optimise cytokine production in response to coincident TCR and TLR agonists. Key words: Neonate immunity . gd T cells . Toll-like receptors Supporting Information available online IntroductionAfter the protected intra-uterine environment, birth exposes the newborn mammal to precipitous encounter with antigens. Although several groups have concluded that lymphocytes from young animals can, under optimal conditions, successfully mount robust immune responses [1][2][3], it is also clear de facto that immune responses in children and young animals are sub-optimal and that neonates and infants are more vulnerable to infections, and respond less well to most vaccines than do older children or adults [4][5][6]. While different studies primarily attribute the problem to intrinsic defects in à These authors contributed equally to this work. 1794T cells or APC, respectively, it is likely that both are impaired in vivo [7].One particularly striking deficit reported in neonatal ab T cells is in IFN-g production, which underpins Th1 responses to intracellular parasites, bacteria and certain viruses. Such defects in conventional T-cell responses have fuelled the hypothesis that gd T cells, that are relatively rare in the blood and lymphoid circulation of adults, may contribute disproportionately to immune function in the young. Supporting this, weanling gd cell-deficient (TCR-d À/À ) mice, relative to wild-type counterparts, show a delayed acquisition of immune resistance to the natural gut pathogen, Eimeria vermiformis ([8] and our unpublished data). There is a similar susceptibility of young TCR-d À/À mice to infection by Cryptosporidium [9]. Provocatively, very early T-cell development is disproportionately di...

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