Papp, Gábor

Szabó, Krisztina

Szekanecz, Zoltán

Zeher, Margit

Rheumatology

University of Debrecen Electronic Archive

For Peer Review
 
 
 
 
 
 
Follicular helper T-cells in autoimmune diseases 
 
 
Journal: Rheumatology 
Manuscript ID: RHE-13-0662.R1 
Manuscript Type: Editorial 
Date Submitted by the Author: n/a 
Complete List of Authors: Papp, Gábor; University of Debrecen Medical Center, Institute of Medicine, 
Department of Clinical Immunology 
Szabó, Krisztina; University of Debrecen Medical Center, Institute of 
Medicine, Department of Clinical Immunology 
Szekanecz, Zoltán; University of Debrecen Medical Center, Institute of 
Medicine, Department of Rheumatology 
Zeher, Margit; University of Debrecen Medical Center, Institute of Medicine, 
Department of Clinical Immunology 
Keywords<br>Please select a 
minimum FIVE keywords from 
the list provided. These 
keywords will be used to select 
reviewers for this 
manuscript.  The keywords in 
the main text of your paper do 
not need to match these 
words.: 
Rheumatoid arthritis < RHEUMATIC DISEASES, Sjogren’s syndrome < 
RHEUMATIC DISEASES, Systematic lupus erythematosus and 
autoimmunity < RHEUMATIC DISEASES, B cells < BASIC & CLINICAL 
SCIENCES, T cells < BASIC & CLINICAL SCIENCES 
  
 
 
Rheumatology
For Peer Review
 
 
Follicular helper T-cells in autoimmune diseases 
 
 
 
Gábor Papp
1
 MD, PhD, Krisztina Szabó
1
, Zoltán Szekanecz
2
 MD PhD DSc  
and Margit Zeher
1
 MD, PhD, DSc 
 
Departments of 
1
Clinical Immunology, and 
2
Rheumatology Institute of Medicine, University 
of Debrecen Medical and Health Science Center, Debrecen, Hungary 
 
Key words: autoimmune diseases, follicular helper T-cell, autoantibody, B-cell activation 
None of the authors have any competing interest. 
Correspondence and reprint request: 
Margit Zeher MD, PhD, DSc 
Department of Clinical Immunology, University of Debrecen Medical and Health Science 
Center, Moricz Zs. str. 22, H-4032 Debrecen, Hungary 
Tel/Fax: +36-52-255-218 Email: zeher@iiibel.dote.hu 
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In autoimmune diseases, the breakdown of immune tolerance leads to the development 
of autoreactive immune responses targeting self-structures, and subsequent tissue and organ 
damage. Although the complex immunobiological mechanisms of autoimmune processes are 
still not fully clear, altered B-cell function and autoantibody production seem to play a special 
role in the development of numerous autoimmune diseases. Understanding the process of B-
cell activation and autoantibody production is particularly important not only for early 
diagnosis but also for development of novel effective treatments.  
Follicular T helper (TFH) cells are special CD4+ T-cells mediating antigen-specific 
naive or memory B cell activation within the B-cell follicles of secondary lymphoid organs. 
TFH cells are generated from peripheral naive CD4+ T-cells in the T-cell zone of these 
lymphoid organs. The differentiation of TFH cells begins with their migration to the border of 
T-cell zone and B-cell follicle. This follicular homing process is directed by B-cell lymphoma 
6 protein (Bcl-6), by coordinating the downregulation of CCR7, a receptor for certain T-zone 
chemokines, and the upregulation of CXCR5, the receptor for CXCL13. CXCL13 is a 
chemokine ligand secreted by follicular stromal cells in B-cell follicles, which attracts primed 
T-cells to the follicle edge, where they interact with antigen-primed B-cells and differentiate 
into TFH cells. Interplay of TFH and activated B-cells is essential for the generation of 
extrafollicular short-lived plasma cells producing low-affinity antibodies, and for germinal 
centre (GC) responses as well. Within GC, TFH cells promote the development of high-affinity 
memory B-cells and long-lived plasma cells by providing survival signals to centrocytes, 
which have undergone somatic hypermutation. Regarding the critical role of TFH cells in B-
cell activation and antibody production, their failure to maintain self-tolerance and potential 
contribution to autoimmunity has drawn much attention. 
Lessons learned from animal models, mainly murine models of systemic lupus 
erythematosus (SLE), shed light on altered TFH profile in autoimmune conditions. 
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Chronologically first, the significance of interleukin 21 (IL-21), now considered the hallmark 
cytokine of TFH cells, was recognized in autoimmunity. Ozaki et al. [1] demonstrated 
enhanced IL-21 production in BXSB-Yaa mice, a model exhibiting lupus-like disease. IL-21 
blockade or IL-21 receptor deficiency in lupus-prone MRL-Fas
lpr
 mice resulted in diminished 
lupus-associated features including IgG deposits in glomeruli, circulating dsDNA 
autoantibodies, total IgG1 and IgG2a production, lymphadenopathy and spontaneous GC 
formation [2,3]. Further studies examining TFH cells directly showed an aberrantly expanded 
TFH population. Interestingly, when Wu et al. [4] investigated the effect of nasal anti-CD3 on 
TFH cells in NZB/WF1 mice, CD4
+
/ICOS
+
/CXCR5
+
 TFH cells obtained from anti-CD3-treated 
mice showed decreased IL-21, IL-17 expression, and induced less IgG, IgG1 or IgG2a anti-
dsDNA antibody production in an in vitro co-culture with naive CD19
+
 B cells. Recent 
observations in autoimmune animal models further enriched our knowledge about the 
development and function of TFH cells. In an elegant study, Linterman et al. [5] investigated 
the deletion of Sap (Sh2d1a) and the loss of one Bcl-6 allele in Roquin
san/san
 (sanroque) mice. 
They found that deletion of one Bcl-6 allele diminished spontaneous GC formation and lupus 
phenotype, moreover the deficiency of the Sap molecule caused dramatic reduction in 
CD4
+
/CXCR5
+
/PD-1
high
 TFH cells, IL-21 production, renal pathology, formation of GC and 
autoantibodies. Moreover, adoptive transfer of sanroque TFH cells into wild-type recipients 
resulted in spontaneous GC formation, underscoring the direct role of TFH cells in the 
development of lupus-associated autoimmunity. Recently, using the IL-27Rα
-/-
 pristane-
induced lupus model, Batten et al. [6] demonstrated that the heterodimeric cytokine IL-27 was 
critical for the function of TFH cells, as well as for normal and pathogenic GC responses. 
Investigations on human autoimmune diseases also suggest that aberrant TFH cell 
development and function can drive autoimmunity. Simpson et al. were the first to 
demonstrate altered TFH proportions in SLE patients. By determining CD4
+
CXCR5
+
ICOS
high 
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and CD4
+
CXCR5
+
PD-1
high
 TFH cells in peripheral blood, they observed an overrepresented 
population of CD4
+
ICOS
high
 and CD4
+
CXCR5
+
ICOS
high
 TFH cells, which showed association 
with the high autoantibody titre and the presence of glomerulonephritis [7]. Subsequently, 
expansion of circulating TFH cells has been reported in patients with various autoimmune 
diseases, such as Sjögren’s syndrome, rheumatoid arthritis, juvenile dermatomyositis and 
autoimmune thyroid disorders. In primary Sjögren’s syndrome, our group demonstrated that 
the elevated circulating CD4
+
/CXCR5
+
/ICOS
+
/PD-1
+
 TFH cell percentages were associated 
with the presence of systemic extraglandular manifestations and anti-SSA/SSB positivity. 
Patients with higher TFH cell proportions had also elevated serum levels of IL-12 and IL-21 
[8]. Maehara et al. [9] investigated the selective localization of Th1, Th2, Th17, regulatory T 
and TFH cells in labial salivary gland biopsies. They found that the expression of TFH and Th2-
related molecules in infiltrating lymphocytes with ectopic GCs was higher than in those 
without ectopic GCs. Recently, elevated circulating TFH cell proportions were detected in SLE 
and corticosteroids down-regulated TFH cell numbers [10].  
Overall, these observations suggest that perturbations to TFH cells potentially 
contribute to numerous human autoimmune diseases. However, it should be noted that 
although circulating CD4
+
/CXCR5
+ 
TFH cells are similar to follicular TFH cells in terms of 
ICOS and PD-1 expression, circulating TFH cells in SLE patients do not express Bcl-6 and IL-
21. This divergence raises an important question: are circulating TFH cells really related to 
classic TFH cells? Albeit the fate of TFH cells generated during GC reaction is still unclear, 
circulating TFH cells may be a special subset of TFH cells which migrated into the systemic 
circulation. Recently, a new hypothesis emerged suggesting that TFH cells can generate 
memory cells. According to Morita et a. [11], circulating CD4
+
/CXCR5
+ 
TFH cells share 
functional properties of TFH cells present in lymphoid organs, and constitute a subset of 
memory TFH cells persisting for a long time in peripheral blood. Upon subsequent antigenic 
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challenge, these memory cells may form TFH cells more quickly and promote GC responses. 
Although in recent years significant progress has been made, further studies are needed to 
better understand the origins and function of TFH cells. TFH cells may be good therapeutic 
targets in these autoimmune diseases [10].  
 
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REFERENCES 
 
1. Ozaki K, Spolski R, Ettinger R et al. Regulation of B cell differentiation and plasma cell 
generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol 2004;173:5361-
71. 
2. Herber D, Brown TP, Liang S, Young DA, Collins M, Dunussi-Joannopoulos K. IL-21 
has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc 
reduces disease progression. J Immunol 2007;178:3822-30. 
3. Rankin AL, Guay H, Herber D et al. IL-21 receptor is required for the systemic 
accumulation of activated B and T lymphocytes in MRL/MpJ-Fas(lpr/lpr)/J mice. J 
Immunol 2012;188:1656-67. 
4. Wu HY, Quintana FJ, Weiner HL. Nasal anti-CD3 antibody ameliorates lupus by 
inducing an IL-10-secreting CD4+ CD25- LAP+ regulatory T cell and is associated 
with down-regulation of IL-17+ CD4+ ICOS+ CXCR5+ follicular helper T cells. J 
Immunol 2008;181:6038-50. 
5. Linterman MA, Rigby RJ, Wong RK et al. Follicular helper T cells are required for 
systemic autoimmunity. J Exp Med 2009;206:561-6. 
6. Batten M, Ramamoorthi N, Kljavin NM et al. IL-27 supports germinal center function 
by enhancing IL-21 production and the function of T follicular helper cells. J Exp Med 
2010;207:2895-906. 
7. Simpson N, Gatenby PA, Wilson A et al. Expansion of circulating T cells resembling 
follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic 
lupus erythematosus. Arthritis Rheum 2010;62:234-44. 
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8. Szabo K, Papp G, Barath S, Gyimesi E, Szanto A, Zeher M. Follicular helper T cells 
may play an important role in the severity of primary Sjögren's syndrome. Clin 
Immunol 2013;147:95-104. 
9. Maehara T, Moriyama M, Hayashida JN et al. Selective localization of T helper subsets 
in labial salivary glands from primary Sjögren's syndrome patients. Clin Exp Immunol 
2012;169:89-99. 
10.  Feng X, Wang D, Chen J et al. Inhibition of aberrant circulating Tfh cell proportions by 
corticosteroids in patients with systemic lupus erythematosus. PLoS One 
2012;7:e51982. 
11. Morita R, Schmitt N, Bentebibel SE et al. Human blood CXCR5(+)CD4(+) T cells are 
counterparts of T follicular cells and contain specific subsets that differentially support 
antibody secretion. Immunity 2011;34:108-21. 
 
 
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Follicular helper T cells in autoimmune diseases

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Follicular helper T cells in autoimmune diseases

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