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Review Article

T follicular helper cell subsets: a potential key player in autoimmunity

Izumi Kurata Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan, Isao Matsumoto Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, JapanCorrespondenceismatsu@md.tsukuba.ac.jp
 & Takayuki Sumida Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
Received 19 Mar 2020
Accepted 23 May 2020
Published online: 17 Jun 2020
In this articleClose

Review Article

T follicular helper cell subsets: a potential key player in autoimmunity

Abstract

Abstract

Follicular helper T (Tfh) cells are one of CD4+ helper T subsets which promote B cell maturation, activation and antigen-specific antibody production. Autoantibodies are hallmarks of autoimmune diseases, and crucial contributions of Tfh cells in development of these diseases are now evident. Deregulation of Tfh activities can contribute to a pathogenic autoantibody production and can play an important role in the promotion of autoimmune diseases. These days multiple researchers reported three subpopulations which has distinct effector functions in Tfh cells: Tfh1, Tfh2 and Tfh17 cells. In this review, we summarize the observed alterations in whole Tfh cells and subset distribution during autoimmune diseases.

1. Introduction

It has been known that T cells are required for effective humoral immune response [1]. Upon stimulation, CD4+ naïve T cells differentiate into T helper (Th) 1, Th2, Th17, follicular helper T (Tfh) and T regulatory (Treg) cells. Each subset requires different signals and cytokines for activation and each subset has a different function in the immune response.

Among them, Tfh cells are characterized as a subset which facilitate T cell-dependent B cell-help. They are localized in B cell follicles and in particular germinal centers (GCs) of secondary lymphoid organs with expression of C-X-C chemokine receptor 5 (CXCR5) [2–4]. CXCR5 is highly expressed on the surface of B cells and binds its ligand C-X-C ligand 13 (CXCL13), which attract them to contact to follicular dendritic cells and form GCs [5]. Surface CXCR5 expression of Tfh cells serves as an attractant into B cell follicles and enable them to cell–cell contact with B cells [4–6]. In addition, Tfh cells express a diverse repertoire of other surface molecules (e.g., programmed death-1 (PD-1), CD40 ligand (CD40L), inducible co-stimulator (ICOS), OX40) and produce interleukin (IL)-21, which promote B cell affinity maturation and differentiation into antibody secreting cells [7]. Tfh-B cell interaction via PD-1 is essential for long-lived plasma cells development [8]. Mice lacking CD40 or CD40L showed impaired GC response and long-term memory [9]. GC B cell failed to survive without ICOS-dependent signals and it led to decrease of plasma cell frequency [10]. OX40 deficiency in Tfh cells caused to B cell differentiation failure and impaired virus-specific antibody responses [11]. IL-21 works not only for Tfh cells proliferation, but also affinity maturation of antibodies in mice [12]. Blockade or deficiency of these costimulatory molecules interrupts a successful humoral response.

Upon Tfh cells, there are distinct subsets that shares same properties as conventional Th1, 2, 17 cells. Especially in autoimmune diseases, an altered repertoire of Tfh cells can contribute to the disease development despite how their fate is determined remains unclear. In this review, we discussed on the potential role of imbalances Tfh subsets in autoimmune diseases.

2. Tfh subsets in a steady state

Human Tfh cells have been first identified in tonsil as a helper T cell subset which helped B cell function and expressed B cell lymphoma-6 (BCL6) as its main transcriptional factor [2–4,13]. These days some Tfh cells are found to be able to simultaneously express other transcriptional factors [14,15] and have the similar cytokine profiles like Th1, 2, 17 and T regulatory cells in addition to IL-21. Conversely, Th1, 2 and 17 cells can be reprogrammed to Tfh-like cells [16]. Epigenetic analysis revealed that loci of BCL6 were ‘opened’ for transcription in every helper T cells subsets, regardless of their differentiation state [16,17]. These phenomena illustrate that Tfh cells have strong plasticity and heterogeneity.

Our understanding of lymphoid Tfh cells is derived largely from studies in mice, mainly because of difficulties in obtaining Tfh cells from human secondary lymphoid organs. However, there exist some differences between human and mice Tfh cells. Of note, the development of the cells might differ between mice and humans. In humans, TGF-β acts with IL-12 and IL-23 to promote expression of Tfh-related molecules, like CXCR5, IL-21 and BCL6 [15]. This is in contrast to mouse CD4+ T cells, in which TGF-β signals suppress expression of IL-21, ICOS and BCL6 [15,18,19]. Thus, the discovery of circulating Tfh (cTfh) cells in human blood [20,21] naturally sparked a new era of investigation by researchers.

CTfh cells also express BCL6, whereas they do lower CXCR5 and PD-1 than follicular Tfh cells [22]. Their TCR sequences overlapped with follicular ones and they had longer residency time, implying that a majority of cTfh cells were recirculating resting cells entered from follicular ones [22]. Further analysis revealed they also had functionally and phenotypically different subsets, identified by expression of CXCR3 and C-C chemokine receptor (CCR) 6 like conventional Th subsets [7,21,23,24] (Figure 1). CTfh1 cells, CXCR3 + CCR6- subset, express T-bet and produce interferon (IFN) γ. CTfh2 cells, CXCR3-CCR6- subset, express GATA3 and produce IL-4 and IL-13. CTfh17 cells, CXCR3-CCR6+ subset, express RORγt and produce IL-17 and IL-22 [21]. All these subsets produce IL-21, which is a characteristic cytokine of Tfh cells. However, not all of them activate B cells and promote production of immunoglobulin. Naïve B cells appear to be stimulated by cTfh2 and cTfh17, but not by cTfh1 cells [21]. These studies suggest cTfh subsets have distinct function in a steady state.

Figure 1. Schema of Tfh subsets and their cytokine production. Tfh: follicular helper T, CXCR: C-X-C chemokine receptor, BCL6: B cell lymphoma-6, IL: interleukin, CCR: C-C chemokine receptor.

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3. Tfh subsets in autoimmunity

A breakdown of immune tolerance leads to emergence of autoimmune diseases. Proliferation of autoreactive B cells and generation of autoantibodies are of crucial importance in the disease development. In this way, Tfh cells could also be possible players in their pathogenesis. The identification of functionally distinct Tfh subsets led us to an idea that their imbalance can be one of the causes of aberrant humoral immune response.

3.1. Rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by multiple and chronic synovitis and bone erosion [25]. Several autoantibodies associated with RA, like rheumatoid factor (RF) and anti-cyclic citrullinated peptides antibodies (ACPAs) are found in peripheral blood and inflamed joints of the patients. They can appear prior to joint inflammation and have a prognostic role [26–29]. Exact pathophysiology of RA is not fully understood. Nevertheless, many of these autoantibodies are somatically mutated IgG antibodies, which indicates the involvement of GC reactions, which suggests a contribution of Tfh cells.

Several studies about murine models have reported importance of Tfh cells in arthritis development. Increase of Tfh cells in secondary lymphoid organs of mice was reported in plural models [30–32]. Among them, we recently reported specific increase of Tfh17 cells in arthritis onset in glucose-6-phosphate isomerase induced arthritis [32]. They seemed to contribute to the disease development by promotion of autoantibody production and regulation of their chemical modification via OX40, which was highly expressed on Tfh17 cells. Another group also reported increase of Th17 cells located in GCs and their role in enhancement of autoantibody function in collagen induced arthritis [33].

In human RA, single cell based analysis showed the existence of Tfh cells also in inflamed joints of the patients [34]. Regarding cTfh cells, Arroyo-Villa et al. [35] has reported the patients have higher frequencies of activated cTfh cells and in particular, of cTfh2 and cTfh17 than healthy controls. We also found that frequency of cTfh17 cells were higher than osteoarthritis patients and had positive correlation with ACPA titers in patients with treatment naïve RA [32]. They also highly expressed OX40 on their surface. Although anti-IL-17 antibody has limited therapeutic effect in RA, we believe not IL-17 itself but Th17-like phenotype is critical in the development of the disease. However, literature data about cTfh and cTfh17 cells frequencies in RA is conflicting. In seven studies, it was observed increased frequencies of cTfh cells in the patients [32,35–40] and some authors found association with the disease activity [36,38–40] and with autoantibody titers [32,36,37,40]. By contrast, other ones did not found the increase of cTfh cells nor differences in the percentages of cTfh1, cTfh2, and cTfh17 subsets in RA patients, compared to healthy controls or patients with undifferentiated arthritis [41,42]. To summarize, cTfh cell, especially cTfh17 cells, could be increased in RA and might have pathogenetic roles (Table 1).

Table 1. Summary of reported cTfh subsets in rheumatoid arthritis and collagen diseases.

3.2. Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) affects multiple organs including kidney, lung, skin, central nerve system (CNS) with increased mortality. It is characterized by appearance of anti-nuclear antibodies in circulation of patients, and lots of evidence showed the association of aberrant Tfh cell with SLE. In addition, the majority of autoantibodies are high-affinity IgG form, which is consistent with observations that showed involvement of GCs in the disease development [66,67].

There are several studies focused on Tfh cells in lupus prone mice. Tfh cells have contributed to the pathogenesis of SLE through ICOS-B7RP-1 pathway in NZB/NZW F1 mice [68]. Hyperactivated Tfh cells were also observed in mice with B lymphocyte-induced maturation protein-1 (Blimp-1)-deficient dendritic cells which shows lupus-like nephritis [69]. In mice which CD4+ cells lack Ets1, Kim CJ et al. [70] reported expansion of Tfh2 cells and their contribution to production of anti-double strand DNA antibodies.

In human studies, increased frequencies of cTfh cells in the patients with association to disease severity were reported [7,43–47] and Tfh-like cells were observed in lupus nephritis lesion [71,72], despite association between them, localized Tfh cells, and disease severity was under discussed [48]. Choi JY et al. [44] reported no difference in balance of cTfh1, cTfh2, and cTfh17 cells compared to controls but correlation with disease severity and cTfh2 cell frequency. Le Coz et al. [49] showed that ratio of cTfh2 and cTfh17 cells are increased in SLE patients and disease activity correlates with the frequency of cTfh2 cells. Conflicting with these two groups, Ma et al. [50] found the increase of cTfh1 cells in the patients than healthy controls. Despite the results differ among each cohort, of particular interest are the trends of cTfh2 cell expansion in SLE, which associated with disease activity (Table 1).

3.3. Sjögren’s syndrome

Primary Sjögren’s syndrome (pSS) is chronic autoimmune disease characterized clinically by dryness of eye and mouth and pathologically by infiltration of lymphocytes into salivary and lacrimal glands, and in which CD4+ T cells and activated B cells seem to play important pathogenic roles [73]. It is widely accepted that B cells play a crucial role in pathogenesis of pSS. Most of pSS patients develop autoantibodies and ectopic GCs are found in the affected tissues. Moreover, they has enhanced risk of B cell lymphoma [74]. These clinical data also indicates a possible important enrollment of Tfh cells.

Several studies demonstrated an increased frequency of cTfh cells in pSS patients [51–54]. Szabó et al. [51] showed increase of cTfh cells especially in the patients with extraglandular manifestations and positive correlation between cTfh cell frequency and anti SS-A/B antibody titers. Li et al. [54] have reported elevated cTfh17 frequency was associated with anti-SS-A antibody titers and European League against Rheumatism Sjögren’s Syndrome Disease Activity Index (ESSDAI), whereas no different frequency between cTfh cell subsets were also reported [55]. Interestingly, frequency of cTfh cells was reported to be reduced after B cell depletion therapy, with a decrease of anti SS-A/B antibody titers and improvement of ESSDAI [56]. In that study, frequencies of cTfh cells were recovered to baseline levels with B cell repopulation. Specific effects of abatacept (CTLA-4 Ig) on Tfh cells are observed during pSS treatment [57]. Abatacept results in significant decrease of cTfh cells and of autoantibody titers. In that study, cTfh cells highly expressed ICOS on their surface than healthy controls. The authors discussed that this interesting effect of abatacept could be the result of normalization of ICOS expression in Tfh cells via reduced T-B cell interaction and less CD28-mediated activation.

Regarding salivary glands, Jin et al. [52] reported increased numbers of localized Tfh cells in the affected glands. When analyzing the expression of cytokines and transcription factors associated with Th subsets (Tfh, Th1, Th2, and Th17 cells), Maehara et al. [75] observed increased expressions of all molecules in pSS patients compared to controls. However, expression of Tfh cell-related molecules was associated with magnitude of lymphocyte infiltration and especially with presence of ectopic GCs.

In summary, reports which described cTfh subset alternation were limited, while many researchers found increase of whole cTfh cells in SS patients. We have to wait for other evidences to discuss which subsets are most critical for the disease (Table 1).

3.4. Systemic sclerosis

Systemic sclerosis (SSc) is a chronic inflammatory and fibrotic disease that affects skin, microcapillary, lung and other internal organs [76]. In patients with SSc, one groups reported increased proportion of cTfh cells with association to disease severity [58] whereas another group found no difference than that of healthy controls [59]. Of particular interest, there appears to be a patient cluster whose Tfh cells are dominant in peripheral blood. This cluster showed severe progression of microcapillary abnormality than other clusters [59]. CTfh subsets were not reported to be altered in the patients [58]. In SSc, B cell secrete disease-specific autoantibodies and could contribute to fibrosis of affected organs. Moreover, Taylor et al. [77] found that skin-infiltrating Tfh-like cells were key drivers of fibrosis in GVHD-SSc model mice. Tfh cells could also be promoters of fibrosis in human SSc.

3.5. Idiopathic inflammatory myopathy

Adult idiopathic inflammatory myopathies (IIMs) includes heterogeneous chronic autoimmune diseases that involve muscle tissue [78]. Among the different subtypes of IIM, dermatomyositis (DM) and polymyositis (PM) are characteristic ones. CTfh cells are expanded in IIM patients compared to controls [60,61]. This expansion was seemed to be caused by the increase of cTfh2 and cTfh17 cells. By contrast, levels of Tfh1 cells are decreased [60]. Another group also found increase of cTfh cells especially in patients with dermatomyositis-associated interstitial lung diseases [61].

3.6. IgG4 related disease

IgG4-related disease (IgG4RD) is characterized by infiltration of CD4+ T cells and IgG4+ plasma cells of various organs. The patients were reported to have higher proportions of cTfh cells, as well as increased proportions of plasmablasts than healthy controls [62]. Specific expansion of cTfh2 cells was reported by multiple researchers, associated with serum IgG4 levels, frequency of plasmablasts, disease activity, and number of affected organs [63–65]. Grados et al. [63] also showed a decrease of cTfh1 frequency in the patients. Akiyama et al. [64] reported that cTfh2 cells have functional responsibility for the differentiation of naïve B cells into plasmablasts and for production of IgG4 in patients with active disease. Despite the role of IgG4 itself in the disease development is not determined, cTfh2 cells could have pathogenicity than other subsets in IgG4RD (Table 1).

3.7. Other autoimmune diseases

3.7.1. Neuroinflammatory diseases

In some neuroinflammatory diseases, contribution of Tfh cells was also reported.

In multiple sclerosis (MS) patients, meningeal inflammation with ectopic GCs was observed by pleural groups [79,80] and Tfh-like cells were found in cerebrospinal fluid (CSF) by recent single cell analysis [81]. In that study, cell set enrichment analysis revealed that Tfh cells could drive B lineage cells expansion in patient CSF [81]. In peripheral blood of patients with relapsing-remitting or secondary progressive forms, cTfh cells expansion was also observed [82–84] with reversibility by a treatment with fingolimod [84]. In these studies, Christensen J et al. [83] reported an increased frequency of cTfh17 cells and a decreased one of cTfh1 cells in the patients. In addition, composition of cTfh subsets was skewed to cTfh1 cells after fingolimod treatment [84].

Neuromyelitis optica spectrum disorders (NMOSD) are also inflammatory demyelinating diseases affecting CNS, characterized by presence of anti auqaporin-4 antibodies [85]. Multiple studies showed increased frequencies of cTfh cells in NMOSD patients [86–88]. They had correlation with disease activity and treatment with methylprednisolone led to a significant decrease of cTfh cells frequency [87]. Untreated NMOSD patients showed an imbalance of cTfh subsets: increase of cTfh17 and (cTfh2 + cTfh17)/cTfh1 ratio [88]. Of interest, anti-CD20 antibody, rituximab, altered the Tfh polarization to that of healthy controls [88].

3.7.2. Psoriasis

Psoriasis is thought to be caused by dysregulation of skin localized immune cells. Frequency of cTfh cells are increased in patients with psoriasis vulgaris, and they are correlated with disease severity and with the accumulation of activated B cells [89,90]. Regarding cTfh cells subsets, Wang Y et al. [91] found a significant increase in cTfh17 cell frequency in the patients, with a trend of increased cTfh2 cells and decreased cTfh1 cells, leading to an increase in (cTfh2 + cTfh17)/cTfh1 ratio. Frequency of cTfh17 cells had correlation with the disease severity and was decreased along with improvement of the disease [91].

4. Conclusion

Despite the possible existence of publication bias, these data we showed demonstrate a key role of altered Tfh subsets in pathogenesis of various autoimmune diseases (Table 1). The patterns of alternation were differed among the diseases, however, many researchers discovered cTfh2 and cTfh17 cells as pathogenetic subsets. In contrast, precise role of cTfh1 cells in autoimmunity remains unclear. In addition, much remains to be learned. It still under investigation whether they serve differently besides promotion of autoantibody production, whether they require different activation pathways, and whether there is plasticity among them. We have to be aware that we do not know if the observed alterations are causative and/or a result of aberrant immune reaction. In addition, of note, peripheral helper T (Tph) cell, which accumulated in inflamed tissues and has comparable B cell help ability to Tfh cells, has attracted attentions these days [92].

Clarifying the detailed biology of Tfh subsets is of particular importance. Answers to these questions could enlighten us to more suitable therapeutic options for autoimmune diseases.

Disclosure statement

The authors report no conflict of interest.

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