PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy.

Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αß T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αß T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1+ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1+ cells, we show that PD-1+Vδ1+ cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1+CD8+ αß T cells. In particular, PD-1+Vδ1+ cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.

Neutrophils Dominate the Cervical Immune Cell Population in Pregnancy and Their Transcriptome Correlates With the Microbial Vaginal Environment.

The cervicovaginal environment in pregnancy is proposed to influence risk of spontaneous preterm birth. The environment is shaped both by the resident microbiota and local inflammation driven by the host response (epithelia, immune cells and mucous). The contributions of the microbiota, metabolome and host defence peptides have been investigated, but less is known about the immune cell populations and how they may respond to the vaginal environment. Here we investigated the maternal immune cell populations at the cervicovaginal interface in early to mid-pregnancy (10-24 weeks of gestation, samples from N = 46 women), we confirmed neutrophils as the predominant cell type and characterised associations between the cervical neutrophil transcriptome and the cervicovaginal metagenome (N = 9 women). In this exploratory study, the neutrophil cell proportion was affected by gestation at sampling but not by birth outcome or ethnicity. Following RNA sequencing (RNA-seq) of a subset of neutrophil enriched cells, principal component analysis of the transcriptome profiles indicated that cells from seven women clustered closely together these women had a less diverse cervicovaginal microbiota than the remaining three women. Expression of genes involved in neutrophil mediated immunity, activation, degranulation, and other immune functions correlated negatively with Gardnerella vaginalis abundance and positively with Lactobacillus iners abundance; microbes previously associated with birth outcome. The finding that neutrophils are the dominant immune cell type in the cervix during pregnancy and that the cervical neutrophil transcriptome of pregnant women may be modified in response to the microbial cervicovaginal environment, or vice versa, establishes the rationale for investigating associations between the innate immune response, cervical shortening and spontaneous preterm birth and the underlying mechanisms.

AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies.

APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.

Immunological visibility: posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway.

Human cytolytic T lymphocytes and natural killer cells can limit tumor growth and are being increasingly harnessed for tumor immunotherapy. One way cytolytic lymphocytes recognize tumor cells is by engagement of their activating receptor, NKG2D, by stress antigens of the MICA/B and ULBP families. This study shows that surface up-regulation of NKG2D ligands by human epithelial cells in response to ultraviolet irradiation, osmotic shock, oxidative stress, and growth factor provision is attributable to activation of the epidermal growth factor receptor (EGFR). EGFR activation causes intracellular relocalization of AUF1 proteins that ordinarily destabilize NKG2D ligand mRNAs by targeting an AU-rich element conserved within the 3' ends of most human, but not murine, NKG2D ligand genes. Consistent with these findings, NKG2D ligand expression by primary human carcinomas positively correlated with EGFR expression, which is commonly hyperactivated in such tumors, and was reduced by clinical EGFR inhibitors. Therefore, stress-induced activation of EGFR not only regulates cell growth but also concomitantly regulates the cells' immunological visibility. Thus, therapeutics designed to limit cancer cell growth should also be considered in terms of their impact on immunosurveillance.

Maternal health and care-seeking behavior in Bangladesh: findings from a national survey.

CONTEXT: Although the reduction of maternal mortality levels is a key Millennium Development Goal, community-based evidence on obstetric complications and maternal care-seeking behavior remains limited in low-resource countries. METHODS: This study presents an overview of key findings from the 2001 Bangladesh Maternal Health Services and Maternal Mortality Survey of ever-married women aged 13-49. The survey collected data on the prevalence of obstetric complications, women's knowledge of life-threatening complications, treatment-seeking behavior and reasons for delay in seeking medical care. RESULTS: Bangladeshi women report low but increasing use of antenatal care, as well as low rates of delivery in a health facility or with the assistance of a skilled provider. Although almost half of women reported having one or more complications during pregnancy that they perceived as life threatening, only one in three sought treatment from a qualified provider. More than three-fourths of women with the time-sensitive complications of convulsions or excessive bleeding either failed to seek any treatment or sought treatment from an unqualified provider. The principal reason cited for failing to seek care for life-threatening complications was concern over medical costs, and pronounced socioeconomic disparities were found for maternal care-seeking behavior in both urban and rural Bangladesh. CONCLUSIONS: Despite these gaps in access to skilled delivery and effective emergency obstetric care, some progress has been made in reducing maternal mortality levels. Improved obstetric care and declining levels of fertility and unwanted pregnancy may have played critical roles in addressing the maternal health care needs of Bangladeshi women.

Implementation of emergency obstetric care training in Bangladesh: lessons learned.

The Women's Right to Life and Health project aimed to reduce maternal morbidity and mortality in Bangladesh through provision of comprehensive emergency obstetric care (EmOC) in the country's district and sub-district hospitals. Human resources development was one of the project's major activities. This paper describes the project in 2000-2004 and lessons learned. Project documents, the training database, reports and training protocols were reviewed. Medical officers, nurses, facility managers and laboratory technicians received training in the country's eight medical college hospitals, using nationally accepted curricula. A 17-week competency-based training course for teams of medical officers and nurses was introduced in 2003. At baseline in 1999, only three sub-district hospitals were providing comprehensive EmOC and 33 basic EmOC, mostly due to lack of trained staff and necessary equipment. In 2004, 105 of the 120 sub-district hospitals had become functional for EmOC, 70 with comprehensive EmOC and 35 with basic EmOC, while 53 of 59 of the district hospitals were providing comprehensive EmOC compared to 35 in 1999. The scaling up of competency-based training, innovative incentives to retain trained staff, evidence-based protocols to standardise practice and improve quality of care and the continuing involvement of key stakeholders, especially trainers, will all be needed to reach training targets in future.

MOET: Bangladesh--an initial experience.

OBJECTIVES: To summarize the quantitative and qualitative immediate assessments of the Managing Obstetric Emergencies and Trauma (MOET) course and to examine the individual changes in score obtained for each of the scenarios. METHODS: Students' knowledge before and after the course was evaluated with a standardized comprehensive questionnaire. RESULTS: All candidates showed an improvement in postcourse, compared to precourse, scores. In the individual score analysis only one scenario showed a non-significant change. The majority of other scenarios showed highly significant improvement between the two scores. CONCLUSION: This paper summarises the development of the first MOET course to be run outside the UK. It demonstrates the reliability of the model-based scenario foundation with a highly significant improvement in knowledge about obstetric emergency management. Further evaluation of longer term practice changes is now required.