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nri.2017.123

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RESEARCH HIGHLIGHTS
Nature Reviews Immunology | Published online 27 Oct 2017; doi:10.1038/nri.2017.123
millan Publishers Limit
Mac
ed
Regulatory T (Treg) cells depend on
IL-2 for their suppressive functions.
A new study in Nature Immunology
shows that, following infection with
influenza virus, some Treg cells downregulate this IL-2 dependency and
differentiate into T follicular regulatory (TFR) cells, which migrate to
B cell follicles to prevent the expansion
of self-reactive B cell clones.
By studying the kinetics of T cell
responses during an acute infection
with influenza virus in mice, the
authors noted that TFR cells (characterized as CD4+FOXP3+BCL‑6+CXCR5hi)
are barely detectable at the peak of
the infection (days 7–15) but accumulate in the lung-draining lymph
nodes during the late phase of the
response (days 30–60). By contrast,
conventional Treg cells rapidly expand
between days 3 and 7 and T follicular
helper (TFH) cells peak between days
7 and 15 and then contract between
days 15 and 30.
Further characterization of
the responding T cell populations
revealed that Treg cells can be divided
into CD25hi and CD25low subsets.
The CD25lowFOXP3+ subpopulation, but not the CD25hiFOXP3+
subpopulation, shows upregulated
expression of markers of TFR cells
following infection
and downregulated
signalling through the
IL-2 LEVELS
high-affinity IL-2 receptor, which is comprised of
CD25 (also known as IL-2Rα)
and IL-2Rβ. Adoptive transfer
experiments confirmed that the
CD25hiFOXP3+ Treg cell subset gives
rise to the CD25lowFOXP3+ TFR cell
subset.
Interestingly, IL-2 production
peaked at day 10 following influenza
virus infection and declined thereafter, so the authors hypothesized that
strong IL-2-induced signals prevent
the differentiation of TFR cells at early
time points. Indeed, mice infected
with influenza virus and treated with
neutralizing IL-2-specific antibodies
showed a marked increase in TFR cell
numbers and a decrease in Treg cell
numbers at day 10 compared with
control mice.
TFR cells are
IL-2R signalling is known to
crucial to avoid
inhibit B cell lymphoma 6 (BCL‑6)
expression by upregulating B lympho- an outgrowth
cyte-induced maturation protein 1
of self-reactive
(BLIMP1) and by favouring the
antibodyformation of T-bet–BCL-6 complexes. The finding that TFR cells that
secreting cells
lacked BLIMP1, but not those that
lacked T-bet, developed at the peak
Treg cells
The IL-2 gauge
ells
TFR c
R E G U L AT O RY T C E L L S
of infection suggests that
IL-2 limits TFR cell differentiation through an intrinsic
BLIMP1‑dependent mechanism.
Finally, the authors used several approaches to show that TFR cells
are crucial to avoid an outgrowth
of self-reactive antibody-secreting
cells (ASCs). In mice that lacked
TFR cells owing to the deletion of
Bcl6 in FOXP3+ cells, influenza
virus-specific germinal centre B cells
accumulated normally following
infection, but there was an increase
in ASC numbers. Similar results
were obtained using recombinant
IL-2 treatment of infected wild-type
mice to prevent the development of
TFR cells. Importantly, the majority of
ASCs in mice lacking TFR cells were
self-reactive rather than influenza
virus-specific, resulting in the
development of antinuclear antibody
responses in the absence of TFR cells.
So, TFR cells limit post-infection
autoimmunity and IL-2 levels control
the temporal regulation of TFR cell
diffferentiation.
NATURE REVIEWS | IMMUNOLOGY
Lucy Bird
ORIGINAL ARTICLE Botta, D. et al. Dynamic
regulation of T follicular regulatory cell responses
by interleukin 2 during influenza infection. Nat.
Immunol. http://dx.doi.org/10.1038/ni.3837 (2017)
www.nature.com/nri
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