830-B 25 FEBRUARY 2022 • VOL 375 ISSUE 6583 science.org SCIENCE
INSIGHTS | PRIZE ESSAY
gens ( 4 ). The organoid cultures recapitulate
the key features of an adaptive immune
response, including T and B cell activation
and differentiation, antigen-specific T and
B cell expansion, somatic hypermutation,
class switching, and specific antibody secre-
tion. Major advantages of the organoid sys-
tem are that both cellular and humoral im-
munity can be studied simultaneously and
longitudinally and that hundreds of condi-
tions can be tested on a single individual’s
cells, revealing intra- and interindividual
sources of immune-response variance. We
showed that tonsil-derived immune organ-
oids stimulated with vaccines produce an-
tibody responses. Further, using B cell re-
ceptor repertoire analysis, we demonstrated
antigen-driven B cell maturation through
germinal centers within the organoids. The
role of T cell help can also be quantified
because T follicular helper cells, which are
critical for B cell selection; T cell activation;
and antigen-specific CD8 T cell expansion
were well recapitulated in the organoids.
My laboratory is now using immune or-
ganoids to study the human adaptive im-
mune response to vaccines and infectious
diseases—including influenza, Epstein
Barr virus, and severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2)—to
understand why some individuals respond
better than others to a given antigen.
Interindividual variation in the magnitude
and quality of the antibody response is
observable, and we are using clinical and
demographic data to explain this variabil-
ity. The spatial organization of lymphoid
tissues plays a key role in orchestrating
adaptive immune responses by regulating
what cell types are sufficiently proximal to
interact and signal one another. The germi-
nal center, where B cells undergo selection
and affinity maturation, is structurally com-
plex. The formation and dissolution of ger-
minal centers is dynamic, with changes oc-
curring within minutes and across multiple
days. Because some features of the germinal
center are preserved in organoid cultures,we have an unprecedented opportunity to
visualize the dynamics of these structures
in human samples.
Our long-term goal for immune organoid
development is to use them to investigate
the mechanisms involved in human adap-
tive immune responses, enable more in-
formed decision-making about what drugs
to take to clinical trial, and accelerate vac-
cine design. jREFERENCES AND NOTES- L. E. Wagar et al., Front. Immunol. 10 , 2239 (2019).
- L. E. Wagar et al., PLOS ONE 6 , e28063 (2011).
- L. E. Wagar, B. Gentleman, H. Pircher, J. E. McElhaney,
T. H. Watts, PLOS ONE 6 , e23698 (2011). - L. E. Wagar et al., Nat. Med. 27 , 125 (2021).
- W. Béguelin et al., Nat. Commun. 8 , 877 (2017).
- A. M. Byers, T. M. Tapia, E. R. Sassano, V. Wittman,
Biologicals 37 , 148 (2009). - C. Giese, U. Marx, Adv. Drug Deliv. Rev. 69-70, 103 (2014).
- C. Giese et al., Artif. Organs 30 , 803 (2006).
- I. Kuzin et al., Biotechnol. Bioeng. 108 , 1430 (2011).
- A. Purwada, A. Singh, Nat. Protoc. 12 , 168 (2017).
- A. Purwada et al., Biomaterials 198 , 27 (2019).
- A. Purwada et al., Biomaterials 63 , 24 (2015).
10.1126/science.abn9652