Debarnot, H. | bioRxiv Science

bioRxiv2024

IL-1β Signaling Modulates T Follicular Helper and Regulatory Cells in Human Lymphoid Tissues

BackgroundDysregulation of the T follicular helper (Tfh) and T follicular regulatory (Tfr) homeostasis in the germinal center (GC) can result in antibody-mediated autoimmunity. While interleukin-1{beta} (IL-1{beta}) has been shown to be an important modulator of the GC response in animal models via the expression of IL-1 agonist (IL-1R1) and antagonist (IL-1R2) receptors on follicular T cells, such regulation has not yet been studied in humans. MethodsWe investigated Tfh and Tfr phenotypes in human secondary lymphoid organs -- namely tonsils, spleens, and mesenteric lymph nodes -- using flow cytometry, single-cell transcriptomics, and in vitro cell culture. We also benchmarked our findings with a cohort of patients with autoimmune and inflammatory diseases. ResultsWe found that Tfh and Tfr cells exhibit organ-specific phenotypes related to their activation status and IL-1 receptor expression. An excess of IL-1R1 over IL-1R2 was linked to the emergence of a unique activated Tfr subset that combines features of both Treg and GC-Tfh cells. Single-cell transcriptomics and in vitro studies showed that IL-1{beta} signaling through IL-1R1 promotes follicular T-cell activation. Inhibiting IL-1{beta} resulted in upregulation of IL-1R1 expression, showing a fine-tuned regulation. In autoimmune patients, high IL-1{beta} and circulating Tfr levels correlated with higher autoantibody levels, linking inflammation, IL-1{beta} signaling, and the Tfr/Tfh balance. ConclusionsOur study underscores the pivotal role of IL-1{beta} in follicular T-cell activation, contributing to pathological antibody production in humans. Targeting IL-1{beta} signaling in Tfh and Tfr cells could offer new treatment strategies for antibody-mediated autoimmune diseases.

immunology↗

bioRxiv2024

Recapitulating memory B cell responses in a Lymphoid Organ-Chip to evaluate mRNA vaccine boosting strategies

Predicting the immunogenicity of candidate vaccines in humans remains a challenge. To address this issue, we developed a Lymphoid Organ-Chip (LO chip) model based on a microfluidic chip seeded with human PBMC at high density within a 3D collagen matrix. Perfusion of the SARS-CoV-2 Spike protein mimicked a vaccine boost by inducing a massive amplification of Spike-specific memory B cells, plasmablast differentiation, and Spike-specific antibody secretion. Features of lymphoid tissue, including the formation of activated CD4+ T cell/B cell clusters and the emigration of matured plasmablasts, were recapitulated in the LO chip. Importantly, myeloid cells were competent at capturing and expressing mRNA vectored by lipid nanoparticles, enabling the assessment of responses to mRNA vaccines. Comparison of on-chip responses to Wuhan monovalent and Wuhan/Omicron bivalent mRNA vaccine boosts showed equivalent induction of Omicron neutralizing antibodies, pointing at immune imprinting as reported in vivo. The LO chip thus represents a versatile platform suited to the preclinical evaluation of vaccine boosting strategies.

immunology↗