An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis.

Peptides presented by HLA-E, a molecule with very limited polymorphism, represent attractive targets for T cell receptor (TCR)-based immunotherapies to circumvent the limitations imposed by the high polymorphism of classical HLA genes in the human population. Here, we describe a TCR-based bispecific molecule that potently and selectively binds HLA-E in complex with a peptide encoded by the inhA gene of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans. We reveal the biophysical and structural bases underpinning the potency and specificity of this molecule and demonstrate its ability to redirect polyclonal T cells to target HLA-E-expressing cells transduced with mycobacterial inhA as well as primary cells infected with virulent Mtb. Additionally, we demonstrate elimination of Mtb-infected cells and reduction of intracellular Mtb growth. Our study suggests an approach to enhance host T cell immunity against Mtb and provides proof of principle for an innovative TCR-based therapeutic strategy overcoming HLA polymorphism and therefore applicable to a broader patient population.

Instability of the HLA-E peptidome of HIV presents a major barrier to therapeutic targeting.

Naturally occurring T cells that recognize microbial peptides via HLA-E, a nonpolymorphic HLA class Ib molecule, could provide the foundation for new universal immunotherapeutics. However, confidence in the biological relevance of putative ligands is crucial, given that the mechanisms by which pathogen-derived peptides can access the HLA-E presentation pathway are poorly understood. We systematically interrogated the HIV proteome using immunopeptidomic and bioinformatic approaches, coupled with biochemical and cellular assays. No HIV HLA-E peptides were identified by tandem mass spectrometry analysis of HIV-infected cells. In addition, all bioinformatically predicted HIV peptide ligands (>80) were characterized by poor complex stability. Furthermore, infected cell elimination assays using an affinity-enhanced T cell receptor bispecific targeted to a previously reported HIV Gag HLA-E epitope demonstrated inconsistent presentation of the peptide, despite normal HLA-E expression on HIV-infected cells. This work highlights the instability of the HIV HLA-E peptidome as a major challenge for drug development.

Sexual and Gender Minority Sleep Health Disparities and Minority Stress in Early Adolescence.

PURPOSE: Sleep is essential to adolescent development. Sexual and gender minority (SGM; e.g., lesbian, gay, bisexual, transgender) adults are at high risk for poor sleep, partially due to minority stress (e.g., discrimination). However, sleep has rarely been studied among SGM adolescents. In a national sample of early adolescents, we analyzed sexual minority (SM) and gender minority (GM) identity, gender incongruence, and gender nonconformity in association with sleep and tested minority and general stressors as mediators. METHODS: We cross-sectionally analyzed data from 10,070 adolescents aged 10-14 in the Adolescent Brain Cognitive Development℠ Study. Using logistic regression models, we analyzed associations between identity (SM and GM), sexual identity discrimination, minority and general stressors (sexual identity discrimination, teasing, and conflict with parents) and sleep health (duration, latency, and disturbance). We used Baron and Kenny's method to test for mediation. RESULTS: Participants reported sexual identity (4% SM, 4% questioning) and gender identity (0.4% GM, 0.6% questioning); 65% were White, 20% were Hispanic, and 52% were assigned male at birth. Compared to heterosexual, SM participants had higher odds of short sleep duration, long sleep latency, and sleep disturbance. GM participants and those reporting gender incongruence and nonconformity had higher odds of long sleep latency and sleep disturbance. Sexual identity discrimination and general social stressors partially mediated some associations. DISCUSSION: SGM participants reported poorer sleep. Minority and general social stressors partially accounted for some disparities. Policies need to address SGM identity-based discrimination and challenge social norms that produce minority stress for SGM early adolescents.

The impact of the COVID-19 pandemic for children in custody: An analysis of inspection reports.

BACKGROUND: Children in custodial settings are a vulnerable group. Prior to the COVID-19 pandemic there were concerns about the safety of children in these settings. COVID-19 has had an impact on everyone but given the vulnerability of children in custody, there were concerns about the impact of COVID-19 restrictions. All custody settings for children are independently inspected and this research aimed to analyse data from inspection reports. Twenty-six inspection reports undertaken between March 2020 and October 2021 were analysed to understand the impact of COVID-19 on delivery of usual care/regime. RESULTS: Data showed that across all site's children spent considerable amounts of time isolated and in some cases, this was deemed to amount to solitary confinement. There was evidence of some positive experiences, in the smaller sites, around COVID-19 slowing the pace of life allowing staff and children could foster relationships. However, in the larger sites, isolation was extreme and COVID-19 policies such as 'bubbles' appear to have created unintended consequences as sites have moved into recovery, leading to increased violence and stress. COVID-19 directly impacted staffing levels. This and the COVID-19 policies to reduce mixing also had an impact on how children's behaviour, welfare and safeguarding was managed. In some larger sites, being COVID-19 secure was prioritised over the needs of the children. CONCLUSIONS: This research highlights the importance of multi-site longitudinal research to understand how children, staff and institution's function. The experiences of children in custody during COVID-19 differed by site type. The research suggests that the larger sites are struggling to keep children safe and there should be a shift towards smaller, more therapeutic environments. More research is needed to understand the longer-term unintended consequences of COVID-19 policy in custody, for these vulnerable children.