RESEARCH ARTICLE SUMMARY
◥IMMUNOLOGY
Identification of a T follicular helper
cell subset that drives anaphylactic IgE
Uthaman Gowthaman, Jennifer S. Chen, Biyan Zhang, William F. Flynn, Yisi Lu,
Wenzhi Song, Julie Joseph, Jake A. Gertie, Lan Xu, Magalie A. Collet,
Jessica D. S. Grassmann, Tregony Simoneau, David Chiang, M. Cecilia Berin,
Joseph E. Craft, Jason S. Weinstein, Adam Williams†, Stephanie C. Eisenbarth†
INTRODUCTION:Cross-linking of high-affinity,
allergen-specific immunoglobulin E (IgE) on
mast cells results in anaphylaxis, a potentially
life-threatening allergic reaction. The cellular
mechanisms that induce B cells to produce
high-affinity IgE to allergens remain poorly
understood and likely differ from those that
generate low-affinity IgE. T follicular helper
(TFH) cells are the primary T cell subset re-
sponsible for directing the affinity, longevity,
and isotype of antibodies produced by B cells;
they have recently been found to be respon-
sible for IgE responses as well. Yet the nature
of the TFHcells that induce high-affinity IgE in
allergic disease remains unclear.RATIONALE:TFHcells guide B cell isotype
switching via cytokine production. Although
interleukin-4 (IL-4) has long been recognized to
guide IgE switching, IL-4 is also a canonical TFH
cell cytokine, expressed even when IgE is not
made. This suggests that although IL-4 is nec-
essary for high-affinity IgE, it is not sufficient,
and additional TFHcell–derived signals are re-
quired. We hypothesized that a distinct but rare
TFHcell population regulates the production ofhigh-affinity IgE. To test this hypothesis, we used
a model of dedicator of cytokinesis 8 (DOCK8)
deficiency, which causes a monogenic form of
allergy associated with aberrant production of
IgE. Comparison of the TFHpopulations present
in this model with wild-type mice immunized
to food and aeroallergens enabled us to iden-
tify the nature of the T cell that induces ana-
phylactic IgE antibody production by B cells.RESULTS:Regardless of immunization condi-
tions, mice with T cell–specificDock8deficiency
made allergen-reactive and anaphylactic IgE.
This was associated with the presence of an
unusual IL-4–and IL-13–producing TFHcell
population in lymph nodes, which we call TFH 13
cells. TFH13 cells demon-
strated a distinctive tran-
scription factor profile,
including expression of
BCL6 and GATA3. TFH 13
cells were also induced in
wild-type mice but only
during immune responses when high-affinity
IgE was made, including during food or aero-
allergen sensitization. These cells were absent
during immune responses lacking high-affinity
IgE, including those induced by bacterial pro-
ducts or helminth infection. Patients who were
allergic to peanut or aeroallergens also had
elevated circulating TFH13 cells. Single-cell RNA
sequencing analysis confirmed that TFH13 cells
were distinct from related T helper 2 (TH2) or
IL-4–expressing TFH2cells.TFH13 cells could
also be distinguished from IL-13–expressing
effector TH2 cells by their subanatomical loca-
tion in the germinal center. Conditional ablation
of TFH13 cells or isolated loss of IL-13 in TFHcells
resulted in impaired high-affinity, anaphylactic
IgE responses to allergens. IgE and IgG1 germi-
nal center B cells, but not naïve B cells, expressed
the receptor for IL-13, suggesting that IL-13
may promote sequential switching of affinity-
matured IgG1+to high-affinity IgE+B cells.CONCLUSION:Our work describes a subset of
T cells necessary for inducing anaphylactic IgE
production to allergens. TFH13 cells and the
molecular pathways operative in this distinc-
tive population represent targets that could
be leveraged diagnostically and therapeutically
for allergies. Furthermore, the identification of
TFH13 cells and the immune context in which
they are induced solves the long-standing
question of how, under rare circumstances,
anaphylaxis-inducing IgE is produced by high-
affinity B cells.▪RESEARCH
Gowthamanet al.,Science 365 , 883 (2019) 30 August 2019 1of1
The list of author affiliations is available in the full article online.
*These authors contributed equally to this work.
†Corresponding author. Email: stephanie.eisenbarth@yale.
edu (S.C.E.); [email protected] (A.W.)
Cite this article as U. Gowthamanet al.,Science 365 ,
eaaw6433 (2019). DOI: 10.1126/science.aaw6433IL-4
IL-21IFNγ
IL-21
IL-4IgMIgMIgG2 IgG1hiIgG1hiIgG1hiIgG1hiIgEloIgEhiPathogen neutralizationPathogen bindingAnaphylaxisIL-4
IL-5
IL-13
IL-21Tfh2BATFHelminthhiTfh13GATA3AllergenBacteria/VirusTfh1
TbetModel of TFHcell–driven antibody production.Distinct TFHcell subsets dictate the
outcome of antibody responses. TFH1 cells elicited to type 1 immunizations (bacterial or
viral infections) do not induce IgE but promote pathogen neutralizing IgGs via production of
IL-21 and interferon-g(IFN-g), with limited IL-4 production. During the type 2 immune
responses to helminth infection, IL-4–and IL-21–producing TFH2 cells are induced, resulting in
production of IgG and low-affinity IgE antibodies but not anaphylaxis. The IgE+B cells in
this case are derived from direct switching from low-affinity IgM+B cells. In contrast, TFH 13
cells are induced during allergic conditions and are necessary for the generation of high-affinity
IgE, which results in anaphylactic responses. The high-affinity IgE+B cells in this case are
derived from sequentially switched and activated IgG1+B cells.
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science.aaw6433
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