Glycosylation-Dependent IFN-γR Partitioning in Lipid and Actin Nanodomains Is Critical for JAK Activation.

Understanding how membrane nanoscale organization controls transmembrane receptors signaling activity remains a challenge. We studied interferon-γ receptor (IFN-γR) signaling in fibroblasts from homozygous patients with a T168N mutation in IFNGR2. By adding a neo-N-glycan on IFN-γR2 subunit, this mutation blocks IFN-γ activity by unknown mechanisms. We show that the lateral diffusion of IFN-γR2 is confined by sphingolipid/cholesterol nanodomains. In contrast, the IFN-γR2 T168N mutant diffusion is confined by distinct actin nanodomains where conformational changes required for Janus-activated tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) activation by IFN-γ could not occur. Removing IFN-γR2 T168N-bound galectins restored lateral diffusion in lipid nanodomains and JAK/STAT signaling in patient cells, whereas adding galectins impaired these processes in control cells. These experiments prove the critical role of dynamic receptor interactions with actin and lipid nanodomains and reveal a new function for receptor glycosylation and galectins. Our study establishes the physiological relevance of membrane nanodomains in the control of transmembrane receptor signaling in vivo. VIDEO ABSTRACT.

Autoimmune regulator (AIRE)-deficient CD8+CD28low regulatory T lymphocytes fail to control experimental colitis.

Mutations in the gene encoding the transcription factor autoimmune regulator (AIRE) are responsible for autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome. AIRE directs expression of tissue-restricted antigens in the thymic medulla and in lymph node stromal cells and thereby substantially contributes to induction of immunological tolerance to self-antigens. Data from experimental mouse models showed that AIRE deficiency leads to impaired deletion of autospecific T-cell precursors. However, a potential role for AIRE in the function of regulatory T-cell populations, which are known to play a central role in prevention of immunopathology, has remained elusive. Regulatory T cells of CD8(+)CD28(low) phenotype efficiently control immune responses in experimental autoimmune and colitis models in mice. Here we show that CD8(+)CD28(low) regulatory T lymphocytes from AIRE-deficient mice are transcriptionally and phenotypically normal and exert efficient suppression of in vitro immune responses, but completely fail to prevent experimental colitis in vivo. Our data therefore demonstrate that AIRE plays an important role in the in vivo function of a naturally occurring regulatory T-cell population.

Community-Based Public Health Vaccination Campaign (VaccinateLA) in Los Angeles' Black and Latino Communities: Protocol for a Participatory Study.

BACKGROUND: The COVID-19 pandemic has significantly affected Los Angeles County and disproportionately impacted Black and Latino populations who experienced disparities in rates of infection, hospitalizations, morbidity, and mortality. The University of Southern California (USC), USC Keck School of Medicine, Southern California Clinical and Translational Science Institute, USC Mann School of Pharmacy and Pharmaceutical Sciences, Annenberg School for Journalism and Communication, and Children's Hospital Los Angeles will launch a collaborative public health campaign called VaccinateLA. OBJECTIVE: VaccinateLA will implement a community-based, community-partnered public health campaign that (1) delivers culturally tailored information about COVID-19 and available vaccines; and (2) addresses misinformation and disinformation, which serves as a barrier to vaccine uptake. The campaign will be targeted to communities in Los Angeles with the highest rates of COVID-19 infection and the lowest vaccination rates. Using these criteria, the campaign will be targeted to neighborhoods located in 34 zip codes in the Eastside and South Los Angeles. The primary aim of VaccinateLA will be to design and deliver an evidence-based multimedia public health campaign tailored for Black and Latino populations. A secondary aim will be to train and deploy community vaccine navigators to deliver COVID-19 education, help individuals overcome barriers to getting vaccinated (eg, transportation and challenges registering), and assist with delivering vaccinations in our targeted communities. METHODS: We will use a community-based, participatory research approach to shape VaccinateLA's public health campaign to address community members' attitudes and concerns in developing campaign content. We will conduct focus groups, establish a community advisory board, and engage local leaders and stakeholders to develop and implement a broad array of educational, multimedia, and field-based activities. RESULTS: As of February 2023, target communities have been identified. The activities will be initiated and evaluated over the course of this year-long initiative, and dissemination will occur following the completion of the project. CONCLUSIONS: Engaging the community is vital to developing culturally tailored public health messages that will resonate with intended audiences. VaccinateLA will serve as a model for how an academic institution can quickly mobilize to address a pressing public health crisis, particularly in underrepresented and underresourced communities. Our work has important implications for future public health campaigns. By leveraging community partnerships and deploying community health workers or promotores into the community, we hope to demonstrate that urban universities can successfully partner with local communities to develop and deliver a range of culturally tailored educational, multimedia, and field-based activities, which in turn may change the course of an urgent public health crisis, such as the COVID-19 pandemic. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/40161.

Chronic Disease Self Management Using a Social Networking PHR/UHR.

This viewpoint paper presents a potential solution to the "information islands" that are holding back PHR/UHR from becoming truly effective diagnostic information care management tools for patients especially those who suffer from chronic diseases. The solution involves integrating patient portal with a diagnostic data interface layer to create a single access point for caregivers and patients.

Peripheral and local human papillomavirus 16-specific CD8+ T-cell expansions characterize erosive oral lichen planus.

Erosive oral lichen planus (OLP) is a chronic, disabling mucocutaneous dysimmune rare disease characterized by mucosal inflammatory erosive lesions with pathological evidence for a marked CD8+ cytotoxic T-lymphocyte (CTL) infiltration. However, the specificity of lesional CTL in OLP has never been analyzed. To investigate the molecular mechanisms underlying dysregulation of T-cell immune responses in patients with OLP, we studied the diversity and antigen specificity of the TCR expressed by CD8+ T cells using dextramer staining, spectratyping, and TCR sequencing in 10 OLP patients undergoing extracorporeal photochemotherapy. Expansions of TCRVß3-bearing CD8+ T cells were found in peripheral blood and in lesional tissues of OLP patients. Spectratyping and sequencing studies identified specific clonotypes in each patient. These expansions were enriched with human papillomavirus 16 (HPV16)-specific CD8+ T cells in HLA-A*0201+ patients as shown by their immune recognition of the E711-20 immunodominant epitope. Under treatment with extracorporeal photochemotherapy, clonotypic CD8+ T-cell expansions decreased in parallel with clinical remission. Altogether, these data establish a link between HPV infection and OLP pathogenesis by identifying a massive clonal expansion of CD8+ T cells with increased frequency of HPV 16-specific CD8+ T cells in OLP patients.