Regulatory T cells and control of the germinal centre response
Arthritis Research & Therapy
Regulatory T cells and control of the germinal centre response
Ine Vanderleyden 1 2
Michelle A Linterman 1
Kenneth GC Smith 0
0 Cambridge Institute for Medical Research , Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY , UK
1 Lymphocyte Signalling and Development, Babraham Institute, Babraham Research Campus , Cambridge CB22 3AT , UK
2 IB Autoimmune Genetics Laboratory, KU Leuven , O&N 2, Campus Gasthiusberg, Herestraat 49, bus 1026, 3000 Leuven , Belgium
Germinal centres (GCs) are specialised lymphoid microenvironments that form in secondary B-cell follicles upon exposure to T-dependent antigens. In the GC, clonal expansion, selection and differentiation of GC B cells result in the production of high-affinity plasma cells and memory B cells that provide protection against subsequent infection. The GC is carefully regulated to fulfil its critical role in defence against infection and to ensure that immunological tolerance is not broken in the process. The GC response can be controlled by a number of mechanisms, one of which is by forkhead box p3 expressing regulatory T (Treg) cells, a suppressive population of CD4+ T cells. A specialised subset of Treg cells - follicular regulatory T (Tfr) cells - form after immunisation and are able to access the GC, where they control the size and output of the response. Our knowledge of Treg cell control of the GC is expanding. In this review we will discuss recent advances in the field, with a particular emphasis on the differentiation and function of Tfr cells in the GC.
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Introduction
The establishment of antigen-specific memory responses
is a key aspect of adaptive immunity that protects the host
against future infections and forms the basis of successful
immunisation. Germinal centres (GCs) are specialised
microenvironments that form in B-cell follicles within
secondary lymphoid organs upon infection or immunisation
with a T-dependent antigen. The effector products of the
GC responses are long-lived, high-affinity antibody
secreting cells and memory B cells [1].
The GC response is initiated when B cells encounter
antigen within the secondary lymphoid tissues. Naïve B
cells recirculate through secondary lymphoid tissues and
enter the B-cell follicle, located underneath the
subcapsular sinus in the lymph nodes and underneath the marginal
zone in the spleen, near sites of antigen entry [2]. In the
follicle, naïve B cells scan for their specific antigen and are
activated following engagement of their B-cell receptor
(BCR) by small soluble antigens directly, by antigen
presentation from subcapsular sinus macrophages [3-5], or by
taking up antigen from follicular dendritic cells (FDC) [6].
After antigen encounter, B cells rapidly upregulate C-C
chemokine receptor type 7 (CCR7), whose ligands
chemokine (C-C motif ) ligand (CCL)21 and CCL19 are expressed
in the adjacent T-cell zone. B cells use this gradient to
migrate towards the T:B border, where they engage in cognate
interactions with CD4+ T-helper type (Th) cells [7]. B cells
then upregulate the orphan G protein-coupled receptor
Epstein–Barr virus-induced gene 2 (EBI2), allowing the
B cell to migrate to the outer edges of the follicle [8,9].
After division, B cells either take part in the
extrafollicular antibody response or enter the B-cell follicle to seed
the GC [10].
B cells that differentiate into extrafollicular plasma cells
secrete class-switched or non-class-switched antibodies in
the early phase of infection and undergo apoptosis in situ
after a few days [11]. This initial and rapid burst of
antibody production is an important component of the early
immune response against infectious organisms and allows
time for the GC to mature without compromising host
defence during this time [12].
B cells that enter the B-cell follicle to seed the GC begin
to divide rapidly, and after this initial clonal expansion the
GC divides into two distinct zones: the dark zone and the
light zone. In the dark zone, B-cell clones undergo somatic
hypermutation, which introduces random point mutations
in the V regions of their immunoglobulin genes [13]. This
process is followed by affinity-based selection in the light
zone that contains FDC bearing immune complexes and
follicular helper T (Tfh) cells. B cells with somatically
mutated BCRs collect antigen from the surface of FDC,
internalise it and present it to Tfh cells in the context of
major histocompatibility complex class II (MHC-II). B
cells with the highest affinity BCRs are able to outcompete
lower affinity B cells for T-cell help, resulting in further
clonal expansion of high-affinity GC B cells and formation
of high-affinity plasma cells and memory B cells [14,15].
This process of mutation and selection that generates
effector B cells with BCRs with increased affinity for antigen
is referred to as affinity maturation, and competition for
Tfh cell help is an essential mediator of this [15].
Follicular helper T ce (...truncated)