ABSTRACT
Lymphoid follicles (LFs) are responsible for generation of adaptive immune responses in secondary lymphoid organs and form ectopically during chronic inflammation. A human model of LF formation would provide a tool to understand LF development and an alternative to non-human primate models for preclinical evaluation of vaccines. Here, we show that primary human blood B- and T-lymphocytes autonomously assemble into ectopic LFs when cultured in a three-dimensional (3D) extracellular matrix gel within an organ-on-a-chip microfluidic device. Dynamic fluid flow is required for LF formation and prevention of lymphocyte autoactivation. These germinal center-like LFs contain B cells expressing Activation-Induced Cytidine Deaminase and exhibit plasma cell (PC) differentiation upon activation. To explore their utility for vaccine testing, autologous monocyte-derived dendritic cells were integrated into LF Chips. The human LF chips demonstrated improved antibody responses to split virion influenza vaccination compared to 2D cultures, which were enhanced by addition of a squalene-in-water emulsion adjuvant, and this was accompanied by increases in LF size and number. When inoculated with commercial influenza vaccine, PC formation and production of anti-hemagglutinin IgG were observed, as well as secretion of cytokines similar to those observed in vaccinated humans over clinically relevant timescales.
Competing Interest Statement
D.E.I. is a founder, board member, scientific advisory board chair, and equity holder in Emulate, Inc.; G.G. and D.E.I. are co-inventors on relevant patent applications. D.R.W. is a founder and has a financial interest in Quanterix Corporation and serves on its Board of Directors.
Footnotes
This version of the manuscript has been revised to update the following: 1. Comparison of immune function between 2D cultures and human LF chip. 2. Correlation between follicle formation and immune function of the human LF chip. 3. Data on the effect of a squalene in water adjuvant on the response of the human LF chip to inactivated influenza vaccination. 4. Text and figures updated to clarify the follicle formation observed on the human LF chip. 5. Authors updated.
