Licensing of natural killer cells by host major histocompatibility complex class I molecules

Self versus non-self discrimination is a central theme in biology from plants to vertebrates, and is particularly relevant for lymphocytes that express receptors capable of recognizing self-tissues and foreign invaders. Comprising the third largest lymphocyte population, natural killer (NK) cells recognize and kill cellular targets and produce pro-inflammatory cytokines. These potentially self-destructive effector functions can be controlled by inhibitory receptors for the polymorphic major histocompatibility complex (MHC) class I molecules that are ubiquitously expressed on target cells. However, inhibitory receptors are not uniformly expressed on NK cells, and are germline-encoded by a set of polymorphic genes that segregate independently from MHC genes. Therefore, how NK-cell self-tolerance arises in vivo is poorly understood. Here we demonstrate that NK cells acquire functional competence through 'licensing' by self-MHC molecules. Licensing involves a positive role for MHC-specific inhibitory receptors and requires the cytoplasmic inhibitory motif originally identified in effector responses. This process results in two types of self-tolerant NK cells--licensed or unlicensed--and may provide new insights for exploiting NK cells in immunotherapy. This self-tolerance mechanism may be more broadly applicable within the vertebrate immune system because related germline-encoded inhibitory receptors are widely expressed on other immune cells.     

Mate fidelity and intra-lineage polygyny in greater horseshoe bats

Mating strategies that lead to increased kinship within socially cooperative groups may offer inclusive fitness benefits to individuals, but can also result in higher levels of inbreeding. Here we show in a sexually segregated bat species that females avoid this conflict through two mating behaviours. First, most females revisit and breed with specific, individual males across years, so that their single offspring born in different years are full siblings. Second, relatives in the maternal line, including mothers and daughters, share breeding partners (intra-lineage polygyny) more often than expected by chance. Although these behaviours increased levels of co-ancestry among colony members, there was no concomitant rise in inbreeding. We suggest that when females engage in mate fidelity and intra-lineage polygyny, kin ties among female roost mates will be strengthened, thereby potentially contributing to social group cohesiveness. Our findings reveal the hidden complexity that can underlie polygynous breeding, and highlight a new potential route by which female mate choice could influence social evolution.     

An array of possibilities for the study of autoimmunity

Since the completion of the sequencing of the human genome, scientific focus has shifted from studying genes to analysing the much larger number of proteins encoded by them. Several proteins can be generated from a single gene depending on how the genetic information is read (transcribed) and how the resultant protein is modified following translation (post-translational modification). Genomic and proteomic technologies are already providing useful information about autoimmune disease, and they are likely to lead to important discoveries within the next decade.     

Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex

Mutations in LMAN1 (also called ERGIC-53) result in combined deficiency of factor V and factor VIII (F5F8D), an autosomal recessive bleeding disorder characterized by coordinate reduction of both clotting proteins. LMAN1 is a mannose-binding type 1 transmembrane protein localized to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC; refs. 2,3), suggesting that F5F8D could result from a defect in secretion of factor V and factor VIII (ref. 4). Correctly folded proteins destined for secretion are packaged in the ER into COPII-coated vesicles, which subsequently fuse to form the ERGIC. Secretion of certain abundant proteins suggests a default pathway requiring no export signals (bulk flow; refs. 6,7). An alternative mechanism involves selective packaging of secreted proteins with the help of specific cargo receptors. The latter model would be consistent with mutations in LMAN1 causing a selective block to export of factor V and factor VIII. But approximately 30% of individuals with F5F8D have normal levels of LMAN1, suggesting that mutations in another gene may also be associated with F5F8D. Here we show that inactivating mutations in MCFD2 cause F5F8D with a phenotype indistinguishable from that caused by mutations in LMAN1. MCFD2 is localized to the ERGIC through a direct, calcium-dependent interaction with LMAN1. These findings suggest that the MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.     

WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion

A key question in systems biology is how diverse physiologic processes are integrated to produce global homeostasis. Genetic analysis can contribute by identifying genes that perturb this integration. One system orchestrates renal NaCl and K+ flux to achieve homeostasis of blood pressure and serum K+ concentration. Positional cloning implicated the serine-threonine kinase WNK4 in this process; clustered mutations in PRKWNK4, encoding WNK4, cause hypertension and hyperkalemia (pseudohypoaldosteronism type II, PHAII) by altering renal NaCl and K+ handling. Wild-type WNK4 inhibits the renal Na-Cl cotransporter (NCCT); mutations that cause PHAII relieve this inhibition. This explains the hypertension of PHAII but does not account for the hyperkalemia. By expression in Xenopus laevis oocytes, we show that WNK4 also inhibits the renal K+ channel ROMK. This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of NCCT. Most notably, the same mutations in PRKWNK4 that relieve NCCT inhibition markedly increase inhibition of ROMK. These findings establish WNK4 as a multifunctional regulator of diverse ion transporters; moreover, they explain the pathophysiology of PHAII. They also identify WNK4 as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis.     

Polarization of the prompt gamma-ray emission from the gamma-ray burst of 6 December 2002

Observations of the afterglows of gamma-ray bursts (GRBs) have revealed that they lie at cosmological distances, and so correspond to the release of an enormous amount of energy. The nature of the central engine that powers these events and the prompt gamma-ray emission mechanism itself remain enigmatic because, once a relativistic fireball is created, the physics of the afterglow is insensitive to the nature of the progenitor. Here we report the discovery of linear polarization in the prompt gamma-ray emission from GRB021206, which indicates that it is synchrotron emission from relativistic electrons in a strong magnetic field. The polarization is at the theoretical maximum, which requires a uniform, large-scale magnetic field over the gamma-ray emission region. A large-scale magnetic field constrains possible progenitors to those either having or producing organized fields. We suggest that the large magnetic energy densities in the progenitor environment (comparable to the kinetic energy densities of the fireball), combined with the large-scale structure of the field, indicate that magnetic fields drive the GRB explosion.     

Inferring the palaeoenvironment of ancient bacteria on the basis of resurrected proteins

Features of the physical environment surrounding an ancestral organism can be inferred by reconstructing sequences of ancient proteins made by those organisms, resurrecting these proteins in the laboratory, and measuring their properties. Here, we resurrect candidate sequences for elongation factors of the Tu family (EF-Tu) found at ancient nodes in the bacterial evolutionary tree, and measure their activities as a function of temperature. The ancient EF-Tu proteins have temperature optima of 55-65 degrees C. This value seems to be robust with respect to uncertainties in the ancestral reconstruction. This suggests that the ancient bacteria that hosted these particular genes were thermophiles, and neither hyperthermophiles nor mesophiles. This conclusion can be compared and contrasted with inferences drawn from an analysis of the lengths of branches in trees joining proteins from contemporary bacteria, the distribution of thermophily in derived bacterial lineages, the inferred G + C content of ancient ribosomal RNA, and the geological record combined with assumptions concerning molecular clocks. The study illustrates the use of experimental palaeobiochemistry and assumptions about deep phylogenetic relationships between bacteria to explore the character of ancient life.