The innate immune system plays a pivotal role in pathogen defense via pattern recognition receptor sensing, initiating responses upon infection or vaccination. Understanding its functional capacity is crucial for deciphering correlates of vaccine efficacy and understanding responses to infection. Here, we developed a holistic approach to study immune function, generating >3,100 readouts across 16 cell types, 18 pattern recognition receptors, and 11 produced cytokines using spectral flow cytometry. To explore geographical variation, we compared Europeans and urban and rural Indonesians. We observed different immune responses, such as increased interleukin (IL)-1β production in rural Indonesians and impaired interferon (IFN) γ production by innate lymphocytes after Toll-like receptor (TLR) 8 stimulation. In Europeans vaccinated with mRNA-1273, baseline IFNγ production by innate lymphocytes correlated with SARS-CoV-2 spike-specific immune responses. In vitro mRNA vaccine stimulation also induced IFNγ production, which was TLR8 dependent and reduced in rural Indonesians. This study highlights functional immune diversity and TLR8's potential role in mRNA vaccine responses.
© 2025 The Author(s).

Natural killer (NK) cells are critical modulators of HIV transmission and disease. Recent evidence suggests a loss of NK cell cytotoxicity during aging, yet analysis of NK cell biology and aging in people with HIV (PWH) is lacking. Herein, we perform comprehensive analyses of people aging with and without HIV to determine age-related NK phenotypic changes. Utilizing high-dimensional flow cytometry, we analyze 30 immune-related proteins on peripheral NK cells from healthy donors, PWH with viral suppression, and viremic PWH. NK cell phenotypes are dynamic across aging but change significantly in HIV and on antiretroviral drug therapy (ART). NK cells in healthy aging show increasing ⍺4β7 and decreasing CCR7 expression and a reverse phenomenon in PWH. These HIV-associated trafficking patterns could be due to NK cell recruitment to HIV reservoir formation in lymphoid tissue or failed mucosal signaling in the HIV-infected gut but appear to be tight delineators of age-related NK cell changes.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation1-3. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)4-7. RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.