Editors' ChoiceIMMUNITY

Visualizing antibody production in a human lymph node in a dish

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Science Translational Medicine  27 Jan 2021:
Vol. 13, Issue 578, eabg5638
DOI: 10.1126/scitranslmed.abg5638

Abstract

Development of a human lymphoid organoid system enables in vitro modeling of immune responses and antibody formation.

Generation of protective antibodies, such as those elicited by infection or vaccination, is the primary function of B lymphocytes, which differentiate into antibody-secreting plasma cells. However, effective antibody responses require B cells to receive instructional signals from other cells, most notably a specialized subset of T cells, T follicular helper (TFH) cells. This primarily occurs in germinal center areas of secondary lymphoid organs, specialized anatomic structures that facilitate interactions between B cells and TFH cells. Most knowledge regarding this process, including how various components and signals interact, have been learned from in vivo studies in laboratory animals. However, animal models do not always accurately or completely reflect human immune biology, leaving critical gaps in knowledge. To overcome this barrier, Wagar et al. recently developed an in vitro human lymphoid organoid system that enables not only direct visualization, but also manipulation, of this process.

Using a technique known as reaggregation culture, lymphoid organoids were generated from human tonsil tissue collected from surgically resected specimens. These organoids were composed of immune and stromal cells consistent with those found in secondary lymphoid organs. Stimulation of reaggregate cultures with live attenuated influenza vaccine resulted in activation and differentiation of B cells into proliferating, antibody-secreting plasmablasts and elicited a concurrent increase in the presence of TFH cells. These cells collected into germinal center–like structures within the organoid, recapitulating in vivo germinal center formation. Importantly, stimulation not only induced production of influenza-specific antibodies, but also promoted class switching and somatic hypermutation, physiologic processes critical for generation of optimally effective antibodies. The efficacy of the induced antibody response was demonstrated by specific increases in influenza-neutralizing antibodies generated by the organoid culture.

The potential utility of this system as a discovery model was demonstrated by the ability to define essential cellular components for antibody production using selective cell subset depletion. A potential extension of this system was also demonstrated in a limited set of experiments using spleen and lung-draining lymph nodes. This may be important because lymphoid organs from other anatomic locations may differ in their cellular composition and prior exposure to antigen. Together, these results demonstrate that this lymphoid organoid system is a robust platform for probing the biology of antibody responses and may be a valuable tool for optimizing vaccine development.

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