Regulation of antibody responses against self and foreign antigens by Tfr cells: implications for vaccine development - Oxford Academic Journals
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Oxford Open Immunology, 2021, 0(0): iqab012
doi: 10.1093/oxfimm/iqab012
Advance Access Publication Date: 16 June 2021
Review Article
REVIEW ARTICLE
Regulation of antibody responses against self and
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foreign antigens by Tfr cells: implications for vaccine
development
Afonso P. Basto1,2 and Luis Graca 2,3,
*
1
CIISA—Centro de Investigaça~ o Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária,
Universidade de Lisboa, Lisboa, Portugal, 2Instituto de Medicina Molecular, Faculdade de Medicina,
Universidade de Lisboa, Lisboa, Portugal, 3Instituto Gulbenkian de Ciência, Oeiras, Portugal
*Correspondence address. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal. Tel: þ351 217999411; Fax:
þ351 217999412:
E-mail: lgraca@medicina.ulisboa.pt
ABSTRACT
The production of antibodies can constitute a powerful protective mechanism against infection, but antibodies can also par-
ticipate in autoimmunity and allergic responses. Recent advances in the understanding of the regulation of germinal
centres (GC), the sites where B cells acquire the ability to produce high-affinity antibodies, offered new prospects for the
modulation of antibody production in autoimmunity and vaccination. The process of B cell affinity maturation and isotype
switching requires signals from T follicular helper (Tfh) cells. In addition, Foxp3þ T follicular regulatory (Tfr) cells represent
the regulatory counterpart of Tfh in the GC reaction. Tfr cells were identified one decade ago and since then it has become
clear their role in controlling the emergence of autoreactive B cell clones following infection and immunization. At the
same time, Tfr cells are essential for fine-tuning important features of the humoral response directed to foreign antigens
that are critical in vaccination. However, this regulation is complex and several aspects of Tfr cell biology are yet to be dis-
closed. Here, we review the current knowledge about the regulation of antibody responses against self and foreign antigens
by Tfr cells and its implications for the future rational design of safer and more effective vaccines.
Key words: T follicular regulatory cells; T follicular helper cells; vaccines; antibodies; germinal centres; autoimmunity.
INTRODUCTION Dysregulated antibody responses are also implicated in the path-
The induction of long-lasting high-affinity antibodies is a major ophysiology of many autoimmune and allergic diseases.
goal in vaccination and underlies the effectiveness of most Therefore, a greater understanding of the mechanisms driving
protective vaccines developed so far [1]. On the contrary, and regulating the production of high-affinity antibodies will
vaccine-induced antibodies with low affinity, or inadequate certainly contribute for a better control of immune-mediated
antibody isotypes, may not only render vaccines ineffective but disorders and for the development of safer and more effective
can also contribute to vaccine-associated immunopathology [2]. vaccines.
Submitted: 29 April 2021; Received (in revised form): 24 May 2021; Accepted: 16 June 2021
C The Author(s) 2021. Published by Oxford University Press.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
12 | Oxford Open Immunology, 2021, Vol. 0, No. 0
The plasma and memory B cells responsible for the produc- receptor, that confers access to the B cell follicle, and the canon-
tion of high-affinity antibodies are generated in microanatomi- ical regulatory transcription factor Foxp3, thus representing the
cal structures—named germinal centres (GCs)—that are formed regulatory counterpart for Tfh cells in the GC reaction [6, 7, 14]
within the B cell follicles of secondary lymphoid tissues upon (Fig. 1). Tfr cells control the emergence of self-reactive antibod-
antigenic stimulation [3]. The role of CD4þ T cells in providing B ies, preventing antibody-mediated autoimmunity and regulate
cell help for antibody production is a long-established knowl- the response against foreign antigens, thereby contributing for
edge in immunology [4]. However, the way we perceive the T–B a fine-tunned affinity maturation of antibody responses [6, 7].
cell interactions underlying this process was revolutionized in Since their discovery, Tfh and Tfr cells became appealing
the last two decades with the identification of specialized effec- targets both for therapeutic interventions to tackle antibody-
tor and regulatory CD4þ T cell subsets that, contrary to classical mediated disorders and for improving vaccine-induced
T helper cells, enter the B cell follicles and the GCs—the T follic- responses. This review discusses the present knowledge on the
ular helper (Tfh) [5] and T follicular regulatory (Tfr) cells [6, 7]. Tfr regulation of antibody responses directed towards self and
Tfh cells are primed by dendritic cells (DCs) in the T-cell foreign antigens, focusing on the implications for the develop-
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areas of secondary lymphoid organs upregulating the chemo- ment of safer and more effective vaccines.
kine receptor CXCR5 and Bcl6—the lineage-defining transcrip-
tion factor of Tfh cells [8–10]. CXCR5 expression facilitates the
migration of pre-Tfh cells towards the T–B border where the in-
REGULATION OF SELF-REACTIVE ANTIBODY
teraction with cognate B cells reinforces their follicular genetic
programme [5]. This reinforcement leads to Tfh migration into
RESPONSES BY TFR CELLS
the GC where Tfh cells play an essential role for the selection Mice and humans devoid of functional Foxp3þ T regulatory cells
of B cell clones producing high-affinity antibodies and for the develop a severe autoimmune syndrome that includes uncon-
differentiation of long-lived plasma and memory B cells [5]. trolled humoral immunity [15–19]. It is thus not surprising
Tfh-driven GC reactions are controlled by Tfr cells, a special- that when a specialized Treg subset with unique access to B cell
ized regulatory T cell population identified 10 years ago [11–13]. follicles was discovered, its specific role in controlling autoanti-
Tfr cells express simultaneously the CXCR5 chemokine body responses was hypothesized [11–13]. In fact, a major
B cell follicle
(b) Inhibitory signals:
IL-2
PD-1 Germinal
CTLA-4 GC
IL-21 (d)
B cells centre
T
T cell zone Interacon
with B cells
B cell (e) Effector mechanisms:
needed for full
differenaon CTLA-4
(a) DC Neurin
Treg Tfr
Tfr Fgl2
F
Foxp3+ Foxp3+ + Physical interference
F
Foxp3
CD25 + + CD25+ IL-10, TGFβ, granzyme B (?)
CD25-
DC priming iniates CXCR5+
CXCR5++
Tfr cell differenaon BCL6+
BCL6++
ICOS+
ICOS++
(c) Immature Tfr cells PD1-+
escape to circulaon PD1++
Foxp3+
Blood Tfr
CD25+
CXCR5+
BCL6-
Lymph node
Figure 1: differentiation, effector mechanisms and phenotypic markers of Tfr cells. Tfr cells differentiate from naive Foxp3þ Treg cells upon DC priming at the T cell
zone of secondary lymphoid tissues (a). The soluble and contact-dependent factors favouring Tfr differentiation are yet to be discovered but signalling via the surface
molecules PD-1 and CTLA-4 and the cytokines IL-2 and IL-21 have been shown to play an inhibitory role in Tfr differentiation (b). Once primed, Tfr cells can either es-
cape to blood circulation maintaining an immature state (c) or, upon interaction with B cells, proceed towards complete maturation as they move towards the GC (d).
In the GC, Tfh cells provide help and select GC B cell clones with mutated BCR genes leading to the production of high-affinity antibodies. This reaction is tightly regu-
lated by Tfr cells through effector mechanisms that include CTLA-4 blocking of CD80/CD86 co-stimulation; secretion of effector molecules that directly act on B cells
and/or Tfh (e.g. neuritin and Fgl2); physical interference on Tfh–GC B cell interactions; other not yet identified or poorly characterized mechanisms (e). The phenotypic
markers defining Tfr cells at the different stages are shown.Basto and Graca | 3
feature of GC reactions is providing the conditions for the that Tfr cells differentiate from Foxp3þ Treg cells within
emergence and selection of B cell clones with increasing affinity lymphoid tissue, originating Tfr cells that fully mature within
towards the foreign antigens that elicit the B cell response [3]. GCs and more immature Tfr cells that enter the blood circula-
However, this process relies on the random somatic hypermu- tion [22, 26] (Fig. 1).
tation of the B-cell receptor (BCR) genes, which may result in Although all these studies point the conventional Treg cells
the emergence of self-reactive antibodies and ultimately lead to as the main precursors of Tfr cells, it has been shown that Tfr
autoimmunity, thus requiring tight regulation [20]. cells can also arise from peripherally induced Treg cells and be
Although the division of labour between non-follicular and specific for the immunizing antigen, particularly in the absence
follicular T regulatory cells in controlling this process is not yet of competition with thymic Treg cells and when specific adju-
fully elucidated [21], it is now clear that Tfr cells play a critical vants are used [33]. However, under physiological competition
role in preventing the emergence of autoantibodies in GCs. with thymic Treg cells the differentiation from induced Treg
This is supported by three main lines of evidence: first, the dem- cells appears to be infrequent [24]. In fact, while following im-
onstration that Tfr cells preferentially derive from thymic munization it is possible to visualize Tfh cells specific for the
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Foxp3þ Tregs, with a self-biased T cell receptor (TCR) repertoire immunizing antigen with an appropriate MHC class II tetramer,
[11–13, 22–26]; secondly, the observation that a specific Tfr dele- antigen-specific tetramer-positive Tfr cells are hardly detected
tion in mouse models leads to the emergence of self-reactive [24]. Furthermore, the restimulation of sorted Tfr cells ex vivo
antibodies and autoimmunity [23, 27–30]; finally, the growing with DCs loaded with immunizing antigen does not lead to pref-
number of human studies finding correlations between the man- erential proliferation or survival when compared with a control
ifestation of autoimmune diseases and quantitative or qualita- antigen [24]. Finally, analysis of the TCR repertoire of Tfr, Tfh
tive alterations in blood Tfr cells of autoimmune patients [31, 32]. and Treg cell populations by sequencing the TCRa-chain gene
from immunized mice that have a fixed TCRb chain shows that
the Tfr pool has a TCR repertoire that more closely resembles
Tfr precursors and antigen-specificity the predominantly self-reactive repertoire of thymic Treg cells
Mouse studies have shown that Tfr cells, as Tfh and GC B cells, [24]. This difference in the Tfh and Tfr repertoire was indepen-
arise in secondary lymphoid tissues upon infection or vaccina- dently confirmed by Ritvo et al. [25], who have also shown, by
tion. We have also observed that Tfr cell numbers increase in TCR sequencing, that Tfh cell responses are predominantly fo-
the blood of healthy adults after influenza vaccination [22]. A cused on foreign antigens, while Tfr cell responses are mostly
central question to elucidate Tfr cell function, and understand directed towards self-antigens.
their mode of action, was thus to clarify whether Tfr cells are Some studies reported that in mucosal-associated lymphoid
specific to the foreign antigen that triggers their differentiation tissues, or under inflammatory conditions, Foxp3þ Treg cells
or, alternatively, preferentially recognize self-antigens. This is- can be converted into Tfh cells [34–36]. Outside mucosal sites, it
sue directly relates with the question of whether Tfr cells derive was also shown, using lineage tracking, that Tfr cells can lose
from natural Tregs (which have a self-biased TCR repertoire) or Foxp3 expression, becoming ex-Tfr cells with diminished sup-
from peripheral naive Tconv cells (which are specific for non- pressive function [14]. When generated in vitro, these ex-Tfr
self antigens). The first three studies describing Tfr cells in 2011 cells lose the Tfr transcriptional programme and show a tran-
investigated the Tfr ontogeny, and all pointed the thymic scriptional signature more similar to Tfh cells [14]. Under these
Foxp3þ cells as the main precursors of Tfr cells [11–13]. conditions, it is anticipated some degree of overlap between the
Linterman et al. [12] observed that, upon immunization, anti- repertoire of Tfh and Tfr cells, although the polarization of Tfh
gen-specific TCR-transgenic CD4þ cells, which do not contain cells from naive precursors is likely to remain the predominant
thymic Treg cells, did not differentiate into Tfr cells when trans- contribution to the overall Tfh pool given the smaller number of
ferred into congenic wild-type (WT) mice. Moreover, when ei- Tfr cells within the follicle.
ther Foxp3þ or Foxp3 thymic CD4SP T cells were transferred
into congenic mice, only the Foxp3þ cells differentiated in Tfr
Autoreactive responses in mice devoid of functional Tfr
cells upon sheep red blood cells (SRBC) immunization. Our
group used T-cell-deficient mice (TCRa/) as recipients of anti-
cells
gen-specific TCR-transgenic CD4þ T cells and thymic Treg cells The demonstration that Tfr cells preferentially differentiate
demonstrating that only the thymic Treg cells could differenti- from thymic Foxp3þ cells, with a TCR repertoire potentially
ate into Tfr cells following immunization with ovalbumin biased towards autoantigens, supports a model where Tfr cells
(OVA)/alum [11]. Chung et al. also used T-cell-deficient (TCRb/ play a role in preventing the generation of autoantibodies. A
) mice as recipient, and co-transferred WT naive CD4þ T cells major advance for the validation of this concept was the recent
and CXCR5-Foxp3þ Treg cells with different congenic markers, development of murine models allowing the conditional deple-
and showed that upon immunization with keyhole limpet tion of Tfr cells by using Foxp3Cre mice with floxed Bcl6 or Cxcr5
haemocyanin (KLH) and complete Freund’s adjuvant (CFA) genes [37]. Indeed, these systems provided the necessary tools
>98% of Tfr cells formed in the host mice originated from for the demonstration that the absence of Tfr cells is sufficient
the CXCR5Foxp3þ Treg cell population [13]. More recently, for the development of autoimmunity in mice [23, 27–30].
Botta et al. [23] have shown that unlike conventional Treg Taking advantage of the specific Tfr sensitivity to interleu-
cells, which are CD25hi, Tfr cells are CD25lo, and thus tested kin-2 (IL-2), Botta et al. first used rIL-2-treatment to deplete Tfr
whether Tfr cells derive from pre-existing CD25hiFoxp3þ or cells in influenza-infected mice and observed that the fre-
CD25loFoxp3þ T cells. The authors quantified Tfr cells 30 days quency of anti-histone IgG antibody-secreting cells (ASCs) in-
after influenza infection in mice that received congenically creased in treated mice, suggesting that a lack of Tfr cells
marked CD25hiFoxp3þ or CD25loFoxp3þ cells and found signifi- results in the development of anti-nuclear antibody responses.
cantly higher numbers in recipients of CD25hiFoxp3þ cells, This was then confirmed in the same study using a Bcl6fl/
fl
thus corroborating the conclusions of previous works using an Foxp3YFP/Cre mice model in which influenza-infected mice
infection model. Our studies with human T cells also show have shown anti-nuclear antibodies 30 days post-infection [23].4 | Oxford Open Immunology, 2021, Vol. 0, No. 0
In Bcl6-floxed systems, the emergence of autoantibodies follicular subsets, and the subclassification of relevant popula-
was observed not only upon a deliberate infection but, in the tions was not always performed (e.g. regulatory versus non-
long-term, also in the steady-state [27, 28]. Tfr-deficient mice regulatory cells among CXCR5þ cells, or CXCR5þ versus CXCR5
have been shown to spontaneously produce anti-dsDNA, anti- among Foxp3þ populations) [31, 32].
nuclear antibodies, anti-salivary gland and anti-nuclear ribonu- Another source of variability in human studies, and possible
cleoprotein/Smith antibodies at 30 weeks of age, and to develop reason for discrepancies in the reported results, is the heteroge-
inflammatory cell infiltrations in the lung, pancreas and sali- neity of the immunopathologic mechanisms or the distinct
vary gland [27]. Gonzalez-Figueroa et al. [28] also detected in- stages of disease among different patients diagnosed with the
creased levels of lupus-associated antibodies against same disease. In fact, our group has shown that the activation
extractable nuclear antigens in the plasma of 15-week-old mice status of Tfh cells and Tfr/Tfh ratio in the blood of Sjögren syn-
and against histone H1 in 25-week-old, as well as autoantibod- drome patients is associated with different features of the dis-
ies directed to exocrine pancreas, stomach, salivary gland and ease [43]. While an increased Tfr/Tfh ratio indicates the
the gastric parietal cell antigens. formation of ectopic lymphoid structures in target organs
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The role of Tfr cells in the development of autoimmunity (namely, the minor salivary glands), the frequency of blood PD-
was further evaluated using the same Bcl6fl/flFoxp3Cre knockout 1þICOSþ Tfh cells correlates with disease activity [43]. These
(KO) strategy in autoimmune mouse models [27, 29]. In findings emphasize the need to take in account the disease het-
Sjögren’s syndrome model, Tfr-depleted mice have shown re- erogeneity when evaluating blood Tfh and Tfr cells subsets, but
duced saliva secretion, elevated serum autoantibodies and tis- also open the possibility for stratification of patients with
sue destruction associated with lymphocytic infiltration in the autoantibody-mediated diseases for a better therapeutical
submandibular gland [27]. In the same line, Tfr-deficient mice management.
revealed elevated anti-dsDNA IgA serum antibodies in a Although these limitations make difficult the interpretation
pristane-induced lupus murine model, although arthritis signs and comparison of results, a growing number of studies are
were not identified in this study [29]. reporting correlations between autoimmune disease and altera-
Vanderleyden et al. [38] developed a different KO strategy in tions on circulating T follicular cells in humans [31]. Regarding
which the Cxcr5 gene is deleted from Foxp3-expressing cells. Tfr cells, a reduced in vitro suppressive function of cells isolated
Interestingly, although Treg cells expressing CXCR5 were suc- from autoimmune patients was reported, and both increased or
cessfully depleted with this system, microscopy studies have decreased numbers of circulating Tfr cells were observed in dif-
shown that Tfr cells, although at lower levels, were still found ferent settings [31, 32]. Overall, these studies indicate that auto-
inside the GCs. In these settings, with about half the numbers of immune patients show increased numbers or overactivated Tfh
follicular and GC Tfr cells than the control mice, the levels of cells and possible quantitative or qualitative alterations in the
anti-dsDNA IgGs in the serum were unchanged after immuniza- Tfr compartment, thereby suggesting the implication of T follic-
tion with 4-hydroxy-3-nitrophenylacetyl (NP)-KLH/alum. ular cells in antibody-mediated autoimmunity in humans.
Finally, using a murine model where cells that simulta- However, a better understanding of the biological role of Tfr and
neously express CXCR5 and Foxp3þ can be depleted by adminis- Tfh in different disease settings is needed to clarify the appar-
tration of diphtheria toxin (Tfr-DTR model), Clement et al. [30] ent contradictions found among different studies. This will be
observed that mice immunized with NP-OVA given DT before essential for a rational modulation of T follicular cells with ther-
GC initiation has increased autoreactive IgG and IgE as detected apeutic purposes in autoimmune patients.
by an autoantigen protein array. Interestingly, some of the auto-
antigens recognized by these antibodies are antigens targeted
by self-reactive antibodies found in patients with systemic lu- REGULATION OF FOREIGN-REACTIVE
pus erythematosus. ANTIBODY RESPONSES BY TFR CELLS
Together, by using different approaches to specifically de-
The differentiation of Tfr cells is triggered by an antigenic stim-
plete Tfr cells and address steady-state, immunizing and infec-
ulus and thus most of the studies evaluating the biology of Tfr
tion settings, the studies unequivocally ascribe a role for Tfr
cells, including those evaluating the Tfr role in autoimmunity,
cells in preventing autoantibody responses and their pathologic
involved the experimental infection of mice or their immuniza-
consequences. This is corroborated by studies in murine models
tion with foreign antigens. In these works, it became clear that
in which Tfr cells were not specifically depleted but where dys-
the absence of Tfr cells leads, not only to the emergence of self-
functional Tfr cells were implicated in the break of self-
reactive antibodies, but also to altered responses to the foreign
tolerance and consequent autoimmunity [39–42].
antigen used to trigger the immune response.
As discussed above, although the immune system can be
manipulated to elicit foreign-specific Tfr cells (particularly in
Tfr cells in human autoimmune diseases the absence of competition with thymic Treg cells) [33], under
While in mice the specific manipulation of Tfr cells made evi- physiological conditions the majority of Tfr clones arise from
dent their role in controlling antibody-mediated autoimmunity, Foxp3þ thymic Tregs and do not recognize the non-self-
the clarification of how Tfh and Tfr cells contribute to the immunizing antigen [11–13, 23, 25]. However, whether and in
course of autoimmune diseases in humans has been more diffi- which conditions the Tfr regulation of antibodies against for-
cult to establish. Due to the limited access to human lymphoid eign antigens occurs via cognate interactions is not yet clear. In
tissues, circulating Tfh and Tfr cells are often used as surrogates fact, this seems to be dispensable as the capacity of Tfr cells to
to assess GC activity. However, circulating Tfr and Tfh cells, al- regulate the effector functions of bystander cells with different
though representing markers of ongoing humoral activity [22], specificity has already been demonstrated. In an in vitro
do not necessarily reflect the alterations occurring in lymphoid antigen-specific suppression assay, Tfr cells sorted from mice
and non-lymphoid tissues. Moreover, these studies have been immunized with NP-OVA or NP-hen egg white lysozyme (HEL)
using different strategies for the identification of circulating T and then cultured, in the presence of NP-OVA, with Tfh and BBasto and Graca | 5
cells from mice immunized with NP-OVA suppressed B cell shape the antigen-specific B cell repertoire, as BCR mRNA se-
class switch recombination and Tfh proliferation independently quencing revealed that Tfr cell-deficient mice used distinct
of the immunizing antigen [44]. heavy-chain variable genes upon influenza infection and HA
Regardless of the specific mechanisms involved, several immunization compared with control mice [45]. The notion that
studies show that Tfr cell manipulation impacts features of the Tfr cells may have a ‘helper’ function on the GC reaction, impor-
antibody response against foreign antigens that are critical for tant for optimizing the response towards foreign antigens, was
vaccine safety and efficacy. These include the magnitude of the also suggested in a lymphocytic choriomeningitis virus infec-
GC response and antibody titres, the affinity of the antibodies tion model in which the IL-10 produced by Tfr cells was shown
and the nature of isotype switch. to contribute for optimal GC development [46]. Another group,
using a murine model of peanut allergy and Bcl6fl/flFoxp3cre
mice, also found that Tfr cells may play a supportive role over
Regulation of the magnitude and specificity of the GC the GC B cells by repressing the development of Tfh cells with
reaction an abnormal cytotoxic phenotype [47].
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The initial studies describing Tfr cells reported larger GCs and Contrary to what was in general observed in the Bcl6-floxed
increased expansion of GC B cells in mice lacking Tfr cells upon systems, the murine models in which Tfr depletion is based on
immunization, suggesting that this population controls the CXCR5 expression revealed either an irrelevant or a positive ef-
magnitude of the GC response [11–13]. However, differences fect of Tfr-depletion over the magnitude of the foreign-antigen-
were found regarding the impact on the specificity of the re- specific response. In the Cxcr5fl/flFoxp3cre-ERT2 model, a reduction
sponse towards the foreign antigen, evaluated either by assess- in Tfr levels to 50–60% neither impact the size of GC, as evaluated
ing the levels of GC B cells that recognize the immunizing by microscopy, nor the numbers of GC B cells and Tfh, either after
antigen or the titres of antigen-specific antibodies. While Chung NP-KLH/alum immunization or influenza infection [38].
et al. and our group observed increased specific responses to- However, in the Tfr-DTR murine model, where CXCR5þFoxp3þ
wards the immunizing antigens in mice devoid of Tfr cells (im- Tfr cells can be depleted through administration of diphtheria
munized with NP-KHL in CFA and OVA/alum, respectively) [11, toxin (thus allowing to interfere in the response at different
13], Linterman et al. [12] found a decreased specific response stages of the GC), total and antigen-specific IgG levels were in-
against the foreign antigen upon SRBC immunization, despite a creased compared with control mice when depletion was in-
larger expansion of Tfh and GC B cells. duced at an early stage of the GC response [30]. Moreover,
More recently, the works using murine models for the condi- different from what was observed by Lu et al. [45] in the influenza
tional depletion of Tfr cells also provided conflicting results on model regarding the memory phase, Tfr-depletion during the
these issues. Most studies using Foxp3cre mice with floxed Bcl6 primary immunization led to increased antigen-specific anti-
reported minor changes in the overall GC reaction of Tfr- body responses upon boosting, 30 days later [30]. In this Tfr-DTR
deficient mice, but all reported qualitative alterations in the murine model, contrasting with the results obtained with early
specific response towards the foreign antigens. Wu et al. [29] ob- Tfr depletion, no differences were found in GC B cells nor in NP-
served that the levels of GC B cells evaluated 10 days after a pri- specific IgG levels when Tfr cells were depleted after the forma-
mary immunization with SRBC were identical to control mice tion of GCs (10–14 days after primary NP-OVA immunization).
and obtained similar results with other types of immunization Although the results diverge in different models, these stud-
and at different time-points. However, despite similar Tfh and ies demonstrate that interfering with Tfr cells may influence
GC B cell responses, the titres of anti-SRBC IgG were signifi- both the magnitude and the specificity of the GC-dependent hu-
cantly decreased in KO mice, while the levels of specific IgA moral response against foreign antigens. The fact that the im-
were increased. The same pattern was observed when mice pact varies according to the time when Tfr cells are specifically
were immunized with NP-KLH/alum [29]. In a similar mouse deleted, suggests that different aspects of the response are con-
model, an OVA prime-boost immunization also resulted in com- trolled at specific stages of the GC reaction [21, 30, 48]. It seems
parable levels of total GC B cells with a reduction in antigen- that the absence of Tfr cells at an early stage of the GC develop-
specific GC B cell from around 20% to 5% when compared with ment has a major impact on the magnitude of the response, as
Tfr-sufficient mice [28]. In an influenza-infection model, Botta shown in the Tfr-DTR model [30] and corroborated by studies in
et al. did not observe a similar decrease on antigenic-specific GC murine models where total Tregs are briefly depleted at an early
B cells or Tfh cells but found a striking impact on the differenti- phase of the induced response [48]. These observations raised
ation of CD138þ ASCs [23]. The overall ASC levels were increased the hypothesis that Tfr cells may play a critical regulatory role
in the absence of Tfr cells, but the frequency of CD138þ ASCs in the B cell follicle even before the emergence of the GC [21, 37].
specific for the influenza virus-nucleoprotein was significantly For the purposes of vaccine design, it will be important to eluci-
reduced [23]. Another study using influenza infection in Bcl6fl/ date in which circumstances a less stringent early Tfr-
fl
Foxp3cre mice also found a negative impact of Tfr deficiency on suppression can promote the production of antibodies specific
the specific response towards the foreign antigens concomitant to the immunizing antigens without compromising the specific-
with insignificant alterations on the general levels of GC B cell, ity of the response. Further investigation is also needed to clar-
Tfh, and Treg compartments [45]. In this study, the Tfr-deficient ify how and at which stages Tfr cells control other features of
mice had reduced haemagglutinin (HA)-specific GC B cells, re- the GC reaction that impacts the specific response to foreign
duced HA-specific ASCs in the bone marrow and reduced IgG antigens, such as the differentiation of GC-derived plasma cells
titres for HA and neuraminidase at 36 days post-infection [45]. or the resolution of the GC reaction. In fact, the divergent results
In the same line, the memory response seemed to be decreased observed in the mentioned studies indicate that Tfr cells may
in the absence of Tfr cells when evaluated through sequential act differently depending on the type of immunization or infec-
immunization with antigenically distinct influenza strains (that tion. For instance, the kinetics of Tfr emergence is delayed in
have different HA head domains but share a conserved stalk do- the context of influenza infection when compared with vaccina-
main, thus allowing simultaneous evaluation of primary and re- tion with a protein or allergic sensitization [23, 28, 30]. This di-
call responses) [45]. Moreover, the authors show that Tfr cells versity on the development kinetics of Tfr cells must be taken6 | Oxford Open Immunology, 2021, Vol. 0, No. 0
in consideration when studying different adjuvants or antigenic model to evaluate the effect of Tfr cells in the class-switch re-
formulations in the context of vaccine design. combination of autoreactive B cells, Clement et al. [30] co-cul-
tured Tfh and Tfr cells sorted from MOG35–55-immunized
Foxp3GFP mice together with B cells isolated from naive IgHMOG
Regulation of affinity maturation mice (that develop MOG-specific B cell receptors) in the pres-
A major function of GC reactions is the generation of plasma ence of recombinant MOG. In these conditions, IgHMOG B cell-
and memory B cells with the ability to produce high-affinity expansion and class-switch recombination induced by Tfh cells
antibodies. This process relies on the somatic mutation of the was suppressed in the presence of Tfr cells.
genes encoding B cell receptors, followed by the selection of B In these systems, the suppression of isotype switch from
cell clones that bind the target antigen with higher affinity [49]. IgD/IgM to IgG may simply reflect a general suppression of the
In line with the notion that Tfr effector mechanisms have a GC response and not a specific reduction of a particular isotype.
suppressive nature over the GC reaction, initial studies reported However, in vivo studies reported that Tfr cell deficiency may
that antibodies produced in the absence of Tfr cells show in- impact differently over different antibody isotypes. Gonzalez-
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creased high-affinity antibodies towards an immunizing hapten Figueroa et al. [28] analysed baseline titres of different sub-
[13]. Later, Fu et al. [27] immunized Bcl6fl/flFoxp3Cre KO mice classes in Bcl6fl/flFoxp3Cre mice and observed higher IgG1, IgE
with NP-KLH and although affinity maturation (evaluated by and IgA in mice lacking Tfr cells, but a reduction in IgG3.
the ratio of anti-NP4/NP29 antibodies) had no clear alterations However, in a similar murine model, Fu et al. [27] found lower
in a primary response, it was significantly increased either for levels of NP29-specific IgG1 in KO mice after immunization with
IgG or IgG2a when the response was boosted. More recently, NP-KLH in CFA, but significantly higher levels of IgG2a, IgG2c
these results were corroborated in another study using also the and IgA antibodies and comparable levels of IgG2b, IgG3 and
Bcl6fl/flFoxp3Cre system, in which KO mice developed less OVA- IgM (although Tfh cells numbers were not changed). The pro-
specific GC B cells upon OVA prime-boost immunization (al- duction of IgG2c was also enhanced in KO mice upon influenza
though total GC B cells were at comparable levels) but the few infection, although total antiviral IgG levels were unchanged
OVA-specific cells had a significantly higher affinity, as deter- [27]. Interestingly, in these settings the IFN-c expression in
mined by OVA gMFI by flow cytometry [28]. CD4þFoxp3Bcl6þ Tfh cells was significantly increased, provid-
However, other studies revealed a positive role of Tfr cells on ing a possible explanation for the differential isotype switch
the affinity maturation process [29, 30, 45, 50, 51]. In a model [27]. Altered cytokine production in Tfh cells in the absence of
where naive CD4þ T cells with Bcl6-deficient or Bcl6-sufficient Tfr cells was also observed by another group upon SRBC immu-
CD25þ Treg cells were co-transferred into T-cell-deficient mice, nization and following an HIV-1 gp120 DNA prime-protein boost
IgA produced in Peyer’s patches from mice lacking Tfr cells had protocol, with PD1hi Tfh cells from Tfr-deficient mice expressing
lower affinity and diversity [50]. Sage et al. [51] also reported higher levels of IFN-c, IL-10 and IL-21 [29]. In a recent study,
that the immunization of mice transferred with CTLA-4- fibrinogen-like protein 2 (Fgl2) was identified as a soluble effec-
deficient Tfr cells shows increased NP-specific IgG titres but tor mechanism secreted by Tfr cells that also regulate Tfh cyto-
with a lower NP2/NP16 ratio, suggesting lower affinity. The kine production (in addition to directly act over GC B cells) and
same profile was observed in the Tfr-DTR mice model when appears to have a specific role in controlling type 2 antibody
CXCR5þ Tfr cells were depleted after immunization with NP- responses [29,42].
OVA in addavax adjuvant (but before the GC formation) and Due to its importance for allergic responses, the regulation
then boosted with NP-OVA in saline buffer 30 days later. After of IgE class switching by Tfr cells has been capturing major at-
boosting, the NP-specific antibody titres were higher in mice tention. Allergen-specific high-affinity IgE may arise by sequen-
that had been Tfr-depleted before GC initiation at priming, but tial switching of affinity-matured IgG1þ B cells [52] and
showed lower NP2/NP16 ratio [30]. In the same line, using a underlies many allergic diseases. IL-4 production by Th2 cells
DNA prime-protein boost vaccine strategy to induce antibody has long been linked to the induction of IgE antibodies [52] but
response against the human immunodeficiency virus (HIV)-1 Tfh cells, that also produce IL-4, have been found to play a cru-
envelope glycoprotein gp120, Wu et al. [29] observed a signifi- cial role in IgE responses as well [53–57]. Recently, a novel Tfh
cant decrease in the avidity of anti-gp120 IgG in Bcl6fl/flFoxp3cre subset—Tfh13—has been identified as being crucial for inducing
mice, as determined by enzyme linked immunosorbent assay anaphylactic IgE production to allergens [30, 52]. Tfh13 cells pro-
(ELISA) with a chaotropic reagent displacement method. Using duce IL-4 and IL-13, express Bcl6 and Gata3, and are transcrip-
similar ELISA methods and also in Bcl6fl/flFoxp3cre mice, Lu et al. tionally different from Th2 or IL-4-expressing Tfh2 cells. Tfh13
[45] found reduced avidity of anti-HA IgGs in Tfr cell-deficient cells are detected in sensitized mice only when high-affinity IgE
mice 36 days after influenza virus infection. is present and a cell population equivalent to mouse Tfh13 was
These studies indicate that, at least in some conditions, Tfr identified in human allergic patients [52]. Mouse models lacking
cells may be important for the emergence of clones with higher Tfr cells (Bcl6- or CXCR5-floxed and Foxp3Cre) revealed the ma-
affinity for the foreign antigens. A possible explanation is that jor role of Tfr cells in controlling IgE responses in different set-
Tfr cells, by limiting the help provided by Tfh cell to GC B cells, tings. In an house dust mite (HDM) mouse model, Tfr cells
impose a higher level of competition on emergent B cell clones, generated in vivo were able to suppress Tfh13-B cell cocultures
thus restricting the positive selection to clones with higher af- in vitro, inhibiting Tfh cell proliferation and B cell switch both to
finity, while limiting the general expansion of B cells in the GC. IgG1 and IgE classes [30]. In vivo, the deletion of Tfr cells in HDM
sensitized mice, although did not impact the overall levels of
the lymphocyte populations of the GC reaction, led to a slight
Regulation of B cell class-switch increase in IgE plasma cells and significantly higher levels of to-
Tfr cells have been shown to impact B cell isotype switch tal and HDM-specific IgE [30]. Moreover, increased inflammation
in vitro. In co-cultures with Tfh and B cells, Tfr cells suppress in the lungs with granulocytes and eosinophils infiltration was
class switch recombination to IgG1, and this effect is reduced observed compared with control mice [30]. In another model of
when Tfr cells are CTLA-4-deficient [51]. Also, in an in vitro Tfr-deficient mice, immunization protocols with intra-Basto and Graca | 7
peritoneal OVA/alum or intra-gastrical peanut sensitization reactive antibodies. The need to preserve this control must be
resulted in increased levels of total and antigen-specific IgE, but taken into account particularly for vaccination of target popula-
not IgG [28]. When re-challenged intravenously, Tfr-deficient tions with a tendency to develop self-reactive antibodies, such
mice showed anaphylactic reactions, succumbing shortly after as autoimmune patients or the elderly. In addition, at least in
challenge, and presenting elevated levels of histamine in circu- some circumstances, Tfr cells seem to play a positive role in the
lation [28]. Importantly, the authors of this study identified a development of high-affinity antibodies, by guaranteeing a high
novel Tfr cell effector mechanism mediated by neuritin. stringency in the Tfh-dependent selection of B cell clones.
Neutitin is a protein produced by Tfr cells that directly targets B Therefore, in the context of vaccine development, the challenge
cells, dampening IgE class switching, suppressing the accumu- for modulating the GC reaction will be to achieve the right bal-
lation of early plasma cells in GCs and hindering the develop- ance between the factors that enhance and control the GC reac-
ment of autoantibodies [28]. In humans, B cell IgE class tion upon immunization to assure the induction of high-quality
switching has also been shown to be inhibited by IL-10-produc- immune responses while avoiding autoreactivity (Fig. 2).
ing T follicular cells, another recently described T follicular cell Rational modulation of Tfr cells in vaccine design will re-
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subset with similarities to mouse Tfr cells that lack Foxp3 ex- quire a better knowledge about the developmental cues driving
pression [58]. Tfr differentiation and their effector mechanisms (Fig. 1). It is
Overall, the different reports show that the Tfr cells can in- known that Tfr cell differentiation requires the priming by DCs
hibit the production of antibodies with different isotypes. It is [44], which involves TCR triggering and costimulatory signals
not yet possible to establish whether there is a preferential iso- through CD28 and ICOS [12, 60], and that B-cell interactions are
type switching influenced by Tfr cells, or simply a preferential needed for completing their terminal differentiation into ma-
reduction of the isotypes that are being predominantly pro- ture GC Tfr cells [12, 22, 44]. However, the soluble and contact-
duced at the time of Tfr suppression. dependent factors that drive Tfr cell differentiation are still
poorly characterized. The cytokines IL-2 [23, 61] and IL-21 [41,
62, 63], as well as PD-1 [60] and CTLA-4 [48, 51] signalling, have
CONSIDERING TFR CELLS IN VACCINE been shown to dampen Tfr cell differentiation and are potential
DEVELOPMENT targets for controlling Tfr maturation. Regarding Tfr cell effector
Neutralizing antibodies are a major hallmark of the most effec- mechanisms, CTLA-4 [48, 51] and, more recently, neuritin [28]
tive vaccines and thus the T follicular cell subsets specialized in and Fgl2 [42] are the molecules that have been better character-
controlling GC reactions readily became obvious targets for im- ized regarding Tfr function. Therefore, CTLA-4, neuritin and
proving vaccine responses. Restraining Tfr cells while promot- Fgl2 are potential targets for the modulation of Tfr function and,
ing Tfh cell differentiation seemed to be a logical strategy to consequently, for GC regulation. Additional regulatory mecha-
enhance long-lived high-affinity antibody responses, which de- nisms established for other Treg subsets—such as IL-10, TGF-b
pend on GC reactions. In this sense, different adjuvants have and granzyme B—were also proposed [46, 64]. Molecular targets
been evaluated in their capacity to alter the Tfh:Tfr ratio [59]. are thus starting to emerge and their modulation in the vaccine
However, it is now clear that the participation of Tfr cells in GC context, particularly in individuals identified as low-
reactions is critical to focus the antibody specificity towards the responders, may be envisaged in the future. For instance, the in-
immunizing antigen while avoiding the emergence of self- clusion of Tfr-targeting molecules in vaccine formulations or
Range to modulate Tfr cell
funcon in vaccinaon
Tfr
X
Tfr
GC regulaon by Tfr cells
↓ GC magnitude ↑→ GC magnitude
↓ Lower Ab responses ↑ auto-reacvity
↑ ASC differenaon
↓ specific ASC
↑↓ Ab affinity
↑↓ Foreign-Ag specificity
↑↓ Ig isotypes
Figure 2: modulation of Tfr cells for improved vaccine efficacy. Reducing the Tfr cell suppressive function over the GC reaction while promoting the differentiation of
Tfh cells is a rational strategy to enhance GC-dependent antibody responses in vaccination. However, the induction of dysfunctional Tfr cells or highly reduced Tfr cell
levels may lead to increased autoreactivity, altered immunoglobulin isotypes and possible lower antibody affinity, thereby resulting in detrimental outcomes. The
challenge for modulating Tfr cells in the context of vaccine design will be to find how and to what extent their suppressive functions can be restrained while preserving
a stringent selection of foreign-reactive high-affinity B cell clones.8 | Oxford Open Immunology, 2021, Vol. 0, No. 0
the administration of Tfr modulators prior or concomitantly to 9. Nurieva RI, Chung Y, Martinez GJ et al. Bcl6 mediates the de-
vaccine inoculation, either locally or systemically, could be con- velopment of T follicular helper cells. Science 2009;325:1001–5.
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tested and several steps must be taken in pre-clinical studies to directs t follicular helper cell lineage commitment. Immunity
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FUNDING 2001;27:68–73.
This work was funded by UTA-EXPL/NPN/0082/2019, EJPRD/ 16. Chatila TA, Blaeser F, Ho N et al. JM2, encoding a fork head-
0003/2019 and LISBOA-01-0145-FEDER-007391, projeto cofi- related protein, is mutated in X-linked autoimmunity–aller-
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nanciado pelo FEDER através POR Lisboa 2020—Programa
17. Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation,
Operacional Regional de Lisboa, do PORTUGAL 2020, e pela
polyendocrinopathy, enteropathy, and X-linked inheritance
~ o para a Ciência e a Tecnologia to L.G.; and by
Fundaça
(IPEX), a syndrome of systemic autoimmunity caused by
~ o para a Ciência e a Tecnologia—PTDC/CVT-CVT/
Fundaça
mutations of FOXP3, a critical regulator of T-cell homeostasis.
31840/2017 to A.P.B.
Curr Opin Rheumatol 2003;15:430–5.
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AUTHORS’ CONTRIBUTIONS
(IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27:
A.P.B. and L.G. jointly contributed to writing, reviewing and edit- 20–1.
ing the manuscript. 19. Wildin RS, Ramsdell F, Peake J et al. X-linked neonatal diabetes
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man equivalent of mouse scurfy. Nat Genet 2001;27:18–20.
CONFLICT OF INTEREST STATEMENT 20. Stebegg M, Kumar SD, Silva-Cayetano A et al. Regulation of
The authors have no conflicts of interest to declare. the germinal center response. Front Immunol 2018;9:2469.
21. Wing JB, Lim EL, Sakaguchi S. Control of foreign Ag-specific
Ab responses by Treg and Tfr. Immunol Rev 2020;296:104–19.
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