Hiam-Galvez, K. J. | bioRxiv Science

bioRxiv2021

Transient dendritic cell activation diversifies the T cell response to acute infection

The precise timing of T cell priming during infection remains unclear. Here, we mapped the cellular dynamics of all immune lineages during acute infection with Listeria monocytogenes (Lm). We identified highly transient DC activation 2 days post-infection that functions as a critical time window for priming effector T cells. Regulation of this transient state was mediated by DC extrinsic IFN{gamma} provided by lymphocytes. Furthermore, antigen-specific T cells that arrive late to the site of priming and miss peak DC activation acquire only memory T cell fates. This temporal regulation of fate is recapitulated by CD8+ DCs ex vivo, suggesting that shifts in activation state of a single antigen presenting cell population alter T cell fates. These results uncover a novel mechanism for temporal regulation of T cell differentiation during a dynamic immune response to acute infection. One-Sentence SummaryThe immune system generates a balanced protective response through rapidly shifting activation states and recruitment of new cells into an ongoing inflammatory landscape.

immunology↗

bioRxiv2020

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense. One Sentence SummaryIn severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.

immunology↗