Killer cell immunoglobulin-like receptor 3DL1-mediated recognition of human leukocyte antigen B

Members of the killer cell immunoglobulin-like receptor (KIR) family, a large group of polymorphic receptors expressed on natural killer (NK) cells, recognize particular peptide-laden human leukocyte antigen (pHLA) class I molecules and have a pivotal role in innate immune responses. Allelic variation and extensive polymorphism within the three-domain KIR family (KIR3D, domains D0-D1-D2) affects pHLA binding specificity and is linked to the control of viral replication and the treatment outcome of certain haematological malignancies. Here we describe the structure of a human KIR3DL1 receptor bound to HLA-B*5701 complexed with a self-peptide. KIR3DL1 clamped around the carboxy-terminal end of the HLA-B*5701 antigen-binding cleft, resulting in two discontinuous footprints on the pHLA. First, the D0 domain, a distinguishing feature of the KIR3D family, extended towards β2-microglobulin and abutted a region of the HLA molecule with limited polymorphism, thereby acting as an 'innate HLA sensor' domain. Second, whereas the D2-HLA-B*5701 interface exhibited a high degree of complementarity, the D1-pHLA-B*5701 contacts were suboptimal and accommodated a degree of sequence variation both within the peptide and the polymorphic region of the HLA molecule. Although the two-domain KIR (KIR2D) and KIR3DL1 docked similarly onto HLA-C and HLA-B respectively, the corresponding D1-mediated interactions differed markedly, thereby providing insight into the specificity of KIR3DL1 for discrete HLA-A and HLA-B allotypes. Collectively, in association with extensive mutagenesis studies at the KIR3DL1-pHLA-B*5701 interface, we provide a framework for understanding the intricate interplay between peptide variability, KIR3D and HLA polymorphism in determining the specificity requirements of this essential innate interaction that is conserved across primate species.     

DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome

Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.     

Hip glands in a natural population of montane voles ( Microtus montanus )

Average linear movement by populations of Dipodomys ordii, Microtus montanus, Perognathus parvus, and Peromyscus maniculatus   was investigated over a 15-month period by live trapping on a low-level, radioactive waste disposal area in Idaho. No significant differences in movement among habitats were observed seasonally, excepting M. montanus in spring. Average linear movements within habitats ranged from 20 to 70 m for all species, but some patterns varied seasonally and among age classes for individual species. Although predation on contaminated small mammals from the disposal area is a vector of radionuclide transport, local movements by these rodents do not appear to be of sufficient magnitude to contribute significantly to redistribution of radioactive particles.     

Reproductive ecology of black-tailed prairie dogs in Montana

Reproductive ecology of black-tailed prairie dogs ( Cynomys ludovicianus ) was studied on the Charles M. Russell National Wildlife Refuge in northeastern Montana (1978–1980 and 1985). Breeding took place from early March through early April in most years. Persistent snow cover and below normal temperatures in February and March of 1978 delayed the start of breeding. Litter size averaged 4.4 but varied significantly among years. Average yearly litter size was correlated (r 2 = 0.986) with summer (June-September) precipitation prior to the breeding season. Largest average yearly litter size (5.0) followed record precipitation, while the smallest average yearly litter size (3.8) followed extreme drought. More than half the yearling females failed to breed while 88% of the females two years and older bred. Testes weights were greatest early in the breeding season and regressed rapidly during April.     

Thermal ecology and activity patterns of the short-horned lizard ( Phrynosoma douglassi ) and the sagebrush lizard ( Sceloporus graciosus ) in southeastern Idaho

A mark - recapture study of the short - horned lizard ( Phrynosoma douglassi ) and the sagebrush lizard ( Sceloporus graciosus ) was performed from 1976 to 1977 in southeastern Idaho. Both species had mean cloacal temperatures of approximately 33 C. However, P. douglassi had more variable cloacal temperatures, particularly during morning and evening periods. This was caused by differences in sleeping sites chosen by the two species. Adults of both species were active from mid - April through late August, with peak activity in June. Juvenile P. douglassi displayed a seasonal activity pattern similar to that of adults. Juvenile S. graciosus were most active later in the year (August), when adults were disappearing. In both species, young - of - the - year appeared in early to mid - August. Adult and juvenile P. douglassi were active during all daylight hours and displayed no activity peaks, whereas young - of - the - year displayed a bimodal activity pattern. Adult and juvenile S. graciosus were active over all daylight hours but had peak activity between 1200 and 1500 h. Ants ( Pogonomyrmex ) were the lizard's principle prey. However, only young - of - the - year P. douglassi had activity patterns that paralleled that of ants on their mounds.         

Tumor carbohydrate antigens and strategies to develop cancer vaccines and drugs

Certain carbohydrate antigens of malignantly transformed cells have been identified as markers for the onset of cancer and have become targets for the development of anticancer vaccine therapies. For tumor antigens, many carbohydrate antigens belong to T-independent (TI) antigens. Carbohydrate conjugated to protein carriers can switch TI antigen to a T-dependent (TD) antigen. Attempts to add an innate immune response element (such as Toll-like receptor ligand) to carbohydrate TI-antigens have also been studied. Glycosylation inhibitors or small interfering RNA have also been used for antitumor and/or antiviral agents. This review aims at describing the vast spectrum of tumor carbohydrate antigens and strategies to develop cancer vaccines and drugs.     

Reciprocal interactions of the intestinal microbiota and immune system

The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks to treat and prevent disease.