ll
Previews
Research Council of Canada under award number
RGPIN-2019-355803. A.K.F. received an Ontario
Graduate Scholarship and Postgraduate Scholar-
ship – Doctoral from the Natural Sciences and En-
gineering Research Council of Canada.
DECLARATION OF INTERESTS
The authors declare no competing interests.
REFERENCES
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T-bet B or not T-bet B, is that the question
in obesity-related metabolic disease?
Michael P. Cancro1,*
1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
*Correspondence: cancro@pennmedicine.upenn.edu
https://doi.org/10.1016/j.cmet.2022.07.008
Obesity is linked to inflammation and downstream metabolic dysregulation. In this issue of Cell Metabolism,
Ha€gglöf et al. show that iNKT cells enable the accumulation of T-bet+ B cells in white adipose tissue, which in
turn produce chemokine and antibody mediators that exacerbate the onset and severity of metabolic
disease.
Although associations between obesity,
inflammatory cytokines, and metabolic
disease have been well established, a
growing literature suggests that these
processes might also involve interactions
with cells of the innate and adaptive im-
mune systems. For example, leukocytes
or lymphocytes infiltrate many target tis-
sues in these diseases, and antibodies
to various self-components are frequently
observed. Against this backdrop, Ha €gglöf
et al. (2022) sought to assess whether B
lymphocytes are involved in obesity-
driven metabolic disease, and to establish
the cellular and molecular interactions
involved. In toto, their findings reveal a
previously unappreciated circuit of inter-
actions between white adipose tissue,
(2020). Severe reactive astrocytes precipitate path-
ological hallmarks of Alzheimer’s disease via
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McWilliams, M.L. (2000). Characterization of the
ototoxicity of difluoromethylornithine and its enan-
the T-bet+ B lymphocyte subset, and
innate natural killer T (iNKT) cells. More-
over, they show that these T-bet+ B cells
are causally related to the onset and
progression of metabolic disease in a
mouse model.
The primary findings driving these
studies are drawn from patient samples
and show that in white adipose tissue
from individuals with obesity, the repre-
sentation of T-bet+ B cells is elevated
and strongly correlated with body mass
index (BMI) and weight. More extensive
analyses of these cells reveal additional
surface and signaling molecules associ-
ated with T-bet+ B cells, including the in-
tegrin CD11c and several indicators of
recent or ongoing activation. Finally, the
Cell Metabolism 34, August 2, 2022 ª 2022 Elsevier Inc. 1081
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authors note that CD1d, a non-canonical
antigen-presenting molecule that inter-
acts preferentially with iNKT cells,
was downregulated on T-bet+ B cells
compared to their T-bet counterparts.
These core observations prompted them
to ask what drives T-bet+ B cell expansion
in this setting and what role they play in
the establishment of obesity-associated
metabolic disease.
T-bet+ B cells have been increasingly
scrutinized over the last decade and are
variously termed age-associated B cells
(Hao et al., 2011; Rubtsov et al., 2011),
double-negative B cells (Jenks et al.,
2018), atypical memory B cells (Obeng-
Adjei et al., 2017), or simply T-bet+ mem-
ory B cells (Winslow et al., 2017). They are
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associated with both microbe-specific
immunity and vaccination but are also
expanded in numerous autoimmune dis-
eases (reviewed in Cancro, 2020). Despite
increasing appreciation for T-bet+ B cells
in these settings, their potential roles in
obesity and metabolic disease have not
been explored in detail. Several groups
have previously reported B cells with
similar characteristics in human adipose
tissue (Frasca et al., 2021), but the obser-
vations reported by Ha €gglöf et al. sub-
stantially extend earlier descriptions.
To interrogate the nature, interactions,
and roles of T-bet+ B cells more precisely
in obesity-related metabolic disease, the
authors turned to a murine model wherein
these features are induced by a high-fat
diet (HFD). Analogous to the findings in
humans, the proportions and numbers of
T-bet+ B cells were expanded in adipose
tissues and spleens of mice fed an HFD.
This was accompanied by elevations in
the levels of circulating IgG2c, the
murine immunoglobulin heavy chain iso-
type characteristically produced by
T-bet+ B cells. Importantly, the expanded
T-bet+ B cells showed phenotypic and
activation characteristics similar to their
human counterparts, including the altered
expression of CD1d. Intrigued by this
observation and given the unique interac-
tions of CD1d with iNKT cells, the authors
directly asked whether iNKT cells might
be crucial for generating adipose tissue
T-bet+ B cells by using iNKT cell-deficient
CD1d1 knockouts. Strikingly, in contrast
to HFD-fed wild-type (WT) mice, neither
the expansion of T-bet+ B cells nor the
increase in IgG2c occurred in iNKT cell-
deficient mice.
To parse the events involved in these in-
teractions, the authors employed in vivo
models in which parameters key to the
generation of T-bet+ B cells could be
manipulated in the context of iNKT recog-
nition of CD1d-presented glycolipid.
Collectively, these experiments show
that the in vivo generation and expansion
of T-bet+ B cells by TLR7-driven activa-
tion require iNKT cells, likely reflecting
cognate interactions via CD1d and subse-
1082 Cell Metabolism 34, August 2, 2022
quent production of IFN-g, a known driver
of T-bet+ B cell fate.
Returning to their core observations,
the authors ultimately asked whether
and how T-bet+ B cells affect the onset
or severity of metabolic disease in the
context of obesity. Using knockout and
adoptive transfer strategies, the authors
show that the absence of T-bet+ B cells
reduces the prevalence and onset of
metabolic disease, and that disease is
restored upon the adoptive transfer of pu-
rified IgG from HFD-fed WT mice. These
key observations forge a causal link be-
tween obesity-associated metabolic dis-
ease and T-bet+ B cells.
In aggregate, these results provide
mechanistic insight into the origin and
role of adipose tissue-associated T-bet+
B cells in metabolic disease. In addition,
they have clear implications for targeting
either the cells themselves or the interac-
tions involved in their generation as
potential interventions. These might
involve directly targeting T-bet+ cells
through unique surface molecules,
leveraging unique metabolic properties,
or blocking the molecular interactions
required for their generation. Whether
such approaches could prevent, arrest,
or reverse disease remains speculative
but constitutes potentially fertile transla-
tional ground.
Several important fundamental ques-
tions remain. Since IgG2c antibodies per
se are implicated, determining the events
and signals that drive T-bet+ B cell differ-
entiation to plasma cells is an important
step in completing the circle. However,
because plasma cells do not express
T-bet, studies probing this question will
likely require genetic tools that afford lon-
gitudinal fate mapping. In a broader
context, these findings raise the question
of whether the T-bet+ B cell subset—
which has already been implicated in
numerous autoimmune and autoinflam-
matory diseases—extends to additional
autoinflammatory diseases related to
obesity and metabolism. For example,
the link between T-bet+ B cells, their anti-
body products, and inflammatory macro-
Previews
phage recruitment suggests this triad
could be involved in other obesity-related
diseases, such as cardiovascular syn-
dromes and atherosclerosis. These and
related questions provide ample opportu-
nity for experimental interrogation going
forward.
DECLARATION OF INTERESTS
The author declares no competing interests.
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