Foxp3+ Treg cells in humoral immunity
Foxp
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James B.Wing
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ShimonSakaguchi
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Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University
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Suita 565-0871
International Immunology, Vol. 26, No. 2, pp. 61-69 reg regulatory function. Treg cells are essential for the maintenance of immune homeostasis and prevention of autoimmunity. In humoral immune responses, loss of Treg cell function causes increased levels of serum autoantibodies, hyper-IgE, spontaneous generation of germinal centres, and enhanced numbers of specialised T follicular helper cells (Tfh cells) controlled by the lineage-defining transcription factor BCL-6 (B-cell lymphoma 6). Recent studies have demonstrated that a subset of Treg cells [T follicular regulatory (Tfreg) cells] are able to co-opt the follicular T-cell program by gaining expression of BCL-6 and travelling to the follicle where they have an important role in the control of expansion of Tfh cells and the germinal centre reaction. However, the mechanisms by which they exert this control are still under investigation. In this review, we discuss the effects of Treg cells on humoral immunity and the mechanisms by which they exert their
Introduction
The generation of high-affinity antibody is critical to
protection from infectious disease and other threats. During the
T-dependent antibody response, antigen-presenting B cells
at the border of the T-cell zone form cognate interactions with
Th cells and, following co-stimulatory interactions, may either
form short-lived extrafollicular plasmablast
cellsresponsible for rapid but low-affinity antibody production (1)or
traverse to the B-cell follicle. Once activated in situ there, B cells
begin to proliferate and form a germinal centre where
longerlasting, high-affinity responses are induced (2,3).
Although germinal centres are critical for the generation of
protective antibody responses, their dysregulation may lead
to autoimmunity (4). A large proportion of B cells are
autoreactive at an early stage of development (5) and, despite
central tolerance mechanisms such as receptor editing,
clonal deletion and anergy (68), autoreactive B cells are still
present in the periphery. Additionally, somatic hypermutation
within the germinal centre allows the generation of
autoreactive B cells during the response to foreign antigens (9) and
also allows chromosomal translocations that have a causative
role in the generation of lymphomas (1012).
As such, it is evident that self-reactive germinal centres
must be controlled to avoid autoimmunity but also that some
level of regulation of even non-self-reactive germinal centres
must be in place. This is achieved by a number of
mechanisms such as antibody feedback (13) and follicle-resident
CD8+ T cells (14,15). However, in this article we will focus on
the contribution of Foxp3-expressing Treg cells to the control
of the humoral response. Various phenotypes of T cells have
immunosuppressive properties, but the best understood are
CD4+CD25+Foxp3+ Treg cells. These cells are critical to the
regulation of humoral immunity as both mice and humans
with loss of Foxp3 function have raised levels of serum
antibodies (16,17). More recently, it has also become clear that
regulate the germinal centre response (1820).
Treg cells are able to travel into the B-cell follicle and directly
Foxp3+ Treg cells make up around 10% of peripheral CD4+ T
cells and have a critical role in the maintenance of immune
self-tolerance and homeostasis (21,22). The function of Treg
cells is controlled by two key features: (i) the expression of
the transcription factor Foxp3 (2325), responsible for the
maintenance of several key phenotypic factors in Treg-cell
function such as CTLA-4 expression and repression of IL-2
production and (ii) the maintenance of Treg-type
epigenetics, a specific DNA hypomethylation pattern that is required
for the stability and full functional capabilities of Treg cells
(26). In cases where expression of Foxp3 is lost, such
as in the scurfy mouse strain and immune dysregulation
polyendocrinopathy enteropathy X-linked syndrome (IPEX)
patients, the resulting loss of Treg-cell function causes a
range of severe immune disorders such as widespread
autoimmunity, immunopathology and lymphoproliferation
In terms of humoral immunity, Foxp3-deficient mice have
uncontrolled germinal centre reactions and large numbers of
plasma cells and T follicular helper cells (Tfh cells) (20,30).
In the K/BxN mouse model of autoantibody-driven
arthritis, loss of Treg-cell function, owing to the introduction of the
Foxp3 scurfy mutation, leads to accelerated production of
pathogenic autoantibodies and accumulation of spleenic
plasma cells (30,31). In humans, B cells from IPEX patients
produce large amounts of autoreactive antibodies (32).
Another characteristic feature of the loss of Foxp3 function
is hyper-IgE in both mice (33) and IPEX patients (29). This
may be partly because of the disproportionate effect of the
loss of Treg-cel (...truncated)