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The extracellular molecular organization of the individual CD3 subunits around the αβ T cell receptor (TCR) is critical for initiating T cell signaling. In this study, we incorporate photo-crosslinkers at specific sites within the TCRα, TCRβ, CD3δ, and CD3γ subunits. Through crosslinking and docking, we identify a CD3ε'-CD3γ-CD3ε-CD3δ arrangement situated around the αβTCR in situ within the cell surface environment. We demonstrate the importance of cholesterol in maintaining the stability of the complex and that the 'in situ' complex structure mirrors the structure from 'detergent-purified' complexes. In addition, mutations aimed at stabilizing extracellular TCR-CD3 interfaces lead to poor signaling, suggesting that subunit fluidity is indispensable for signaling. Finally, employing photo-crosslinking and CD3 tetramer assays, we show that the TCR-CD3 complex undergoes minimal subunit movements or reorientations upon interaction with activating antibodies and pMHC tetramers. This suggests an absence of 'inactive-active' conformational states in the TCR constant regions and the extracellular CD3 subunits, unlike the transmembrane regions of the complex. This study contributes a nuanced understanding of TCR signaling, which may inform the development of therapeutics for immune-related disorders., Competing Interests: Disclosure and competing interests statement. AN declares no competing interests. MK serves on the scientific advisory boards of Genentech and Merck and Co. and received research support from Merck Sharp & Dohme Corp., a subsidiary of Merck and Co., Inc., Genentech, Biogen, Novartis and the Mark Foundation., (© 2024. The Author(s).)

Objective: To compare "hybrid immunity" (prior COVID-19 infection plus vaccination) and post-vaccination immunity to SARS CoV-2 in MS patients on different disease-modifying therapies (DMTs) and to assess the impact of vaccine product and race/ethnicity on post-vaccination immune responses., Methods: Consecutive MS patients from NYU MS Care Center (New York, NY), aged 18-60, who completed primary COVID-19 vaccination series ≥6 weeks previously were evaluated for SARS CoV-2-specific antibody responses with electro-chemiluminescence and multiepitope bead-based immunoassays and, in a subset, live virus immunofluorescence-based microneutralization assay. SARS CoV-2-specific cellular responses were assessed with cellular stimulation TruCulture IFNγ and IL-2 assay and, in a subset, with IFNγ and IL-2 ELISpot assays. Multivariate analyses examined associations between immunologic responses and prior COVID-19 infection while controlling for age, sex, DMT at vaccination, time-to-vaccine, and vaccine product., Results: Between 6/01/2021 and 11/11/2021, 370 MS patients were recruited (mean age 40.6 years; 76% female; 53% non-White; 22% with prior infection; common DMT classes: ocrelizumab 40%; natalizumab 15%, sphingosine-1-phosphate receptor modulators 13%; and no DMT 8%). Vaccine-to-collection time was 18.7 (±7.7) weeks and 95% of patients received mRNA vaccines. In multivariate analyses, patients with laboratory-confirmed prior COVID-19 infection had significantly increased antibody and cellular post-vaccination responses compared to those without prior infection. Vaccine product and DMT class were independent predictors of antibody and cellular responses, while race/ethnicity was not., Interpretation: Prior COVID-19 infection is associated with enhanced antibody and cellular post-vaccine responses independent of DMT class and vaccine type. There were no differences in immune responses across race/ethnic groups., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: Critical illnesses are a major cause of morbidity and mortality in The Gambia, yet national data on critical care capacity is lacking., Materials and Methods: We surveyed eight of the eleven government-owned health facilities providing secondary and tertiary care in The Gambia's public health sector. At each hospital, a designated respondent completed a questionnaire reporting information on the presence of an intensive care unit, the number of critical care beds where available, monitoring equipment, and the ability to provide basic critical care services at their respective hospitals., Results: The response rate was 88% (7/8 hospitals). Only one hospital had a dedicated intensive care unit with eight ICU beds, resulting in an estimated 0.4 ICU beds/100,000 population in the country. All hospitals reported treating more than 50 critically ill patients a month, with trauma, obstetric emergencies, hypertensive emergencies and stroke accounting for the leading causes of admission respectively. The country lacks any trained specialists and resources to diagnose and treat critically ill patients., Conclusions: The Gambia has a very low ICU bed capacity and lacks the human resources and equipment necessary to diagnose and treat the large number of critically ill patients admitted to public hospitals in the country., (Copyright © 2018 Elsevier Inc. All rights reserved.)