immune system has the peculiar ability to respond to foreign substances
(or antigens) by producing antibody molecules that bind to these
antigens with extremely high affinity and a remarkable degree of
specificity. In order to achieve this high level of affinity, B cells –
the cells that produce antibodies – must undergo a series of steps that
culminate in the generation of an anatomical structure known as the
germinal center (GC). Within this structure, B cells introduce random
mutations into their antibody genes and, in a process reminiscent of
Darwinian evolution, B cells that have acquired affinity-enhancing
mutations proliferate, and are eventually directed to differentiate
into antibody-producing plasma cells or memory cells that can re-expand
upon future contact with the same antigen.
It is this process that
allows vaccines to work, and that makes us immune to catching certain
diseases more than once. On the flip side, failures in the GC reaction
can result in the production of high- affinity antibodies against
innocuous substances or even components of one’s own body – leading to
allergies and autoimmune diseases such as lupus and rheumatoid
arthritis. Furthermore, when misplaced the mutations introduced during
the GC reaction can cause genetic lesions that may ultimately lead to
lymphomas and other malignancies.
|A germinal center reaction in a lymph node
immunized mouse. It is within this structure that B cells mutate their
antibody genes, in a process that ultimately leads to the generation of
In the Victora lab, we combine
a number of cutting-edge techniques – from the development of novel
mouse models to intravital multiphoton microscopy – to shed light on
the intricacies of the GC reaction and its regulation. For example,
using multiphoton-based geotagging of GC cells in a newly developed
photoactivatable mouse, we have been able to define the cellular and
molecular characteristics of different subpopulations of GC B cells, as
well as their dynamic behavior and its relationship to selection. The
characteristics we defined in mice are now being used in human studies
to better understand the events leading to B cell lymphoma. We believe
that unveiling the molecular mechanisms of the GC reaction will be
essential if we wish to design better vaccines, develop treatments for
allergies and autoimmune diseases, and dissect the molecular basis of
JMJ,* Mesin L,* Pasqual G, Targ S, Jacobsen JT, Mano YM, Chen CS, Weill
JC, Reynaud CA, Browne EP, Meyer-Hermann M, Victora G. Visualizing
antibody affinity maturation in germinal centers. Science, 18
Feb 2016 (epub ahead of print). DOI: 10.1126/science.aad3439
Victora GD*, Wilson PC*. Germinal center selection and the antibody response to influenza. Cell. 2015 Oct 22;163(3):545-8.
Pasqual G, Angelini A, Victora GD. Triggering Positive Selection of Germinal Center B Cells by Antigen Targeting to DEC-205. Methods Mol Biol. 2015;1291:125-34.
Victora GD. SnapShot: the germinal center reaction. Cell. 2014 Oct 23;159(3):700-700.e1.
Victora GD & Mesin L. Clonal and Cellular Dynamics in Germinal Centers. Curr Op Immunol. 2014, 28:90-96.
Victora GD. ILCs in the zone. Nat Immunol. Mar 19;15(4):313-4.
Victora GD. Stop, Go, and Evolve. Science. Dec 6;342(6163):1186.
Z, Gitlin AD, Targ S, Jankovic M, Pasqual G, Nussenzweig MC*, Victora
GD*. In vivo dynamics of Tfh cells in Germinal Centers. Science. Aug
D*, Victora GD*, Ying CY, Phan
RT, Saito M, Nussenzweig MC, Dalla-Favera R.The
proto-oncogene MYC is required for selection in the germinal center and
cyclic reentry. Nat Immunol. 2012 Nov;13(11):1083-91
Dominguez-Sola D*, Deroubaix S, Holmes AB, Dalla-Favera R, Nussenzweig
MC. Identification of human germinal center light and dark zone cells
and their relationship to human B cell lymphomas. Blood. 2012 Sep
Meyer-Hermann M, Mohr
E, Pelletier N, Zhang Y, Victora GD*,
Toellner K-M* A novel theory of
germinal center B cell selection, division, and exit. Cell Reports.
2012 Jul 26;2(1):162-74.
Victora GD*, Nussenzweig, MC*.
Germinal Centers. Annu Rev Immunol. 2012;30:429-57.
N, Victora GD, Meredith M,
Feder R, Dong B, Kluger C, Yao K, Dustin ML,
Nussenzweig MC, Steinman RM, Liu K. Flt3L controls the development of
radiosensitive dendritic cells in the meninges and choroid plexus of
the steady-state mouse brain. J Exp Med. 2011 Aug 1;208(8):1695-705.
Schwickert TA*, Victora GD*,
Fooksman DR, Kamphorst AO, Mugnier MR,
Gitlin AD, Dustin ML, Nussenzweig MC. A dynamic T cell-limited
checkpoint regulates affinity-dependent B cell entry into the germinal
center. J Exp Med. 2011 Jun 6;208(6):1243-52.
Schwickert TA, Fooksman DR, Kamphorst AO, Meyer-Hermann M,
Dustin ML, Nussenzweig MC. Germinal center dynamics revealed by
multiphoton microscopy with a photoactivatable fluorescent reporter.
Cell. 2010 Nov 12;143(4):592-605.
Fooksman DR, Schwickert TA, Victora GD,
Dustin ML, Nussenzweig MC,
Skokos D. Development and migration of plasma cells in the mouse lymph
node. Immunity. 2010 Jul 23;33(1):118-27.
Liu K, Victora GD, Schwickert
TA, Guermonprez P, Meredith MM, Yao K,
Chu FF, Randolph GJ, Rudensky AY, Nussenzweig M. In vivo analysis of
dendritic cell development and homeostasis. Science. 2009 Apr
* equal contribution
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