CXCR4 and CXCR5 Orchestrate Dynamic Germinal Center Reactions and May Contribute to the Pathogenesis of Systemic Lupus Erythematosus

www.nature.com/cmi Cellular & Molecular Immunology

CORRESPONDENCE CXCR4 and CXCR5 orchestrate dynamic germinal center reactions and may contribute to the pathogenesis of systemic lupus erythematosus

Bing-xuan Wu1, Li-dan Zhao1 and Xuan Zhang 1 Cellular & Molecular Immunology (2019) 16:724–726; https://doi.org/10.1038/s41423-019-0244-y

In a previous publication in Cellular and Molecular Immunology, Zhao IL-21 and/or CD40L (Fig. 1). Relying on the timely orchestration of et al.1 showed data from patients with treatment-naïve systemic relative CXCR4/CXCR5 expression, interzonal reciprocating move- lupus erythematosus (SLE), demonstrating the clinical significance ments of GC B cells are generated, which is critical for B cell affinity and possible mechanisms of the aberrant expression of the maturation and autoreactivity elimination and is thus indispensable chemokine receptor CXCR4 on lupus B cells. In this commentary, for healthy GC formation and reaction.7 The aberrant expression of we will discuss the roles of CXCL12-CXCR4 and CXCL13-CXCR5 pairs these chemokines and their corresponding receptors may lead to and related signaling pathways in guiding dynamic germinal center dislocation of GC B cells, impaired affinity maturation, ineffective (GC) reactions and B cell selection and describe how their selection, and subsequent differentiation into autoantibody- dysregulation may contribute to the pathogenesis of SLE. producing plasma cells. The unsuccessful downregulation of CXCR4 B cells play a central role in the pathogenesis of SLE as the may block the reentry of GC B cells to LZs, leading to impaired precursors of autoantibody-secreting cells, powerful antigen- selection and release of autoreactive B cells (Fig. 1). The CXCR5/ presenting cells and cytokine producers.2 Although antibody- CXCL13 axis is required for the compartmentalization of GC LZ, secreting cells (ASCs) could derive extrafollicularly, GC is believed overcoming spatial separation between GC B cells and CXCL13+ + to be the main site for generating long-lived plasma cells and FDCs or CXCR5 TFH cells to promote cell–cell interactions (Fig. 1). A memory B cells, which are overactivated in SLE and capable of previous study implicated chemokine dysregulation and the producing pathogenic autoantibodies persistently.3 In GC, B cells development of autoimmune diseases, showing that a subgroup are subdued to affinity-driven evolution and selection, followed by of CXCR4+ plasma cells coexpressing TLR4 was increased in the clonal expansion or deletion. It remains to be elucidated how peripheral blood and renal tissues of both SLE patients and lupus these autoreactive B cells could survive clonal deletion in GC and mice and was capable of producing anti-dsDNA associated with escape into peripheral circulation. Failure of appropriate B cell severe renal damage.8 In addition, Søren et al.9 showed that once receptor (BCR) repertoire trimming in GC may originate from tolerance was broken for one autoantigen, epitope spreading imbalanced programming intrinsically, impaired function of helper occurred, leading to broader targeting of B cells to self-antigens and cells extrinsically and abnormal translocation and immigration the formation of self-sustained autoreactive GCs, which is the associated with intrinsic and extrinsic signals. Numerous studies hallmark of abnormal immune response in SLE. have addressed the roles of BCRs, toll-like receptors (TLRs) and Although evidence is still far from certain, the CXCR4-CXCL12 and intracellular signaling pathways, as well as chemokines and their CXCR5-CXCL13 axis and their downstream signaling mediators are specific receptors, in regulating B cells escape from stringent GC assumed to be crucial participants in the pathogenesis of SLE, in negative selection, subsequent differentiation into plasma cells which TFH cells are closely intertwined. Through costimulatory and their exit into the periphery.3–5 molecules, such as inducible costimulator and programmed cell GCs have exquisite zonal architecture, and the dynamic death protein-1 (PD-1), IL-21 production and the downstream translocation of GC B cells between dark zones (DZs) and light modulation of B cell lymphoma 6 (Bcl-6) and B lymphocyte-induced zones (LZs) are mediated by chemokines and their receptors. GC B maturation protein 1 (Blimp1) activation, TFH cells program B cell cells are centroblasts and centrocytes in the DZs and LZs, expansion, plasma cell differentiation, and BCR reediting. TFH cells respectively. Centroblasts expressing high levels of CXCR4 are could also act as an important resource for local B cell-activating sequestered in DZs, undergo rapid proliferation and somatic factor (BAFF) production within GCs. Excessive BAFF drives the hypermutation within the network of reticular cells expressing development of autoreactive B cells, which in turn promotes TFH cell CXCL12, whereas CXCR4loCXCR5hi centrocytes are recruited to LZs expansion, leading to spontaneous autoreactive GC formation. The by CXCL13-expressing follicular dendritic cells (FDCs) and subdued expansion and aberrant activation of TFH cells have been implicated to antigen-driven-selection through interactions with FDCs and T in the pathogenesis of SLE.10 6 11 follicular helper (TFH) cells. FDCs present native antigens to Sander et al. demonstrated that phosphoinositide 3-kinases centrocytes with newly mutated BCRs, and then TFH cells recognize (PI3K) signaling and the transcription factor forkhead box protein and sense the intensity of the processed antigens presented O1 (FOXO1) were important antagonistic regulators of GC by centrocytes and determine their fate by providing signals, such as reactions, including GC polarization and cellular selection.

1Department of Rheumatology and Clinical Immunology, Clinical Immunology Center, Medical Epigenetics Research Center, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College Hospital, 100730 Beijing, China Correspondence: Li-dan Zhao ([email protected]) or Xuan Zhang ([email protected]) Received: 5 May 2019 Accepted: 11 May 2019 Published online: 3 June 2019

Dark zone Light zone GC

- Centroblasts (CXCR4hi) - Centrocytes (CXCR5hi) - Proliferation - Class switching - Somatic hypermutation - Affinity selection - FOXO1 ↑ - PI3K ↑

Reticular cells FDC

MHC II CXCL12 CXCL13 Apoptosis CXCR4 BCR CXCR5 PD-1L PD-1 CXCR5 Proliferation CXCR4↓ CXCR5↑ MHC II TCR CD40 CD40L Somatic B7 CD28 hypermutation ICOSL ICOS

T Long-lived plasma cells Centrocytes IL-21R FH Centroblasts IL-21

CXCR4↑ CXCR5↓

CXCR4XCCR4↓ Memory B cells 1234567890();,:

Autoreactive B cells Blood vessel

Fig. 1 CXCR4 and CXCR5 orchestrate dynamic GC reactions. The germinal center (GC) consists of two distinct areas known as light zones (LZs) and dark zones (DZs), which are orchestrated by chemokines and their speciﬁc receptors, especially CXCL12-CXCR4 and CXCL13-CXCR5 pairs. + + CXCL13 follicular dendritic cells (FDCs) are located in the LZs and sequester CXCR5 centrocytes and follicular helper T cells (TFH) into the LZs, while CXCL12+ reticular cells segregate CXCR4hi centroblasts in the DZs. Centroblasts (GC B cells in DZs) proliferate and undergo somatic hypermutation in DZs, followed by CXCR4 downregulation and cycling back to LZs, where centrocytes (GC B cells in LZs) undergo afﬁnity- driven selection through interactions with FDCs and TFH cells. Failed downregulation of CXCR4 may block the reentry of B cells to LZs, leading to the impaired selection and release of autoreactive B cells. Activated PI3K signaling and the transcription factor FOXO1, as antagonistic regulators of GC reactions, are mainly restricted to DZs and LZs, respectively

Accordantly, Dalla-Favera et al.12 demonstrated that FOXO1 components contributes to the disordered GC architectural expression and PI3K activity in GC B cells were virtually exclusive polarity and autoreactive GC formation. Signaling molecules, such and restricted to DZs and LZs, respectively (Fig. 1), and that FOXO1 as CD40L and IL21, downstream pathways, including PI3K-AKT and was required for GC DZ programming, B cell afﬁnity maturation JAK-STAT, as well as transcriptional factors, such as BCL6, Blimp1, and class switch recombination. These authors also suggested and FOXO1, are proposed to be involved in skewing GC dynamics that FOXO1 may contribute to CXCR4 transcriptional activation. and B cell selection, and these molecules altogether fuel the Interestingly, Zhao et al.1 showed that the dysregulation of progression of autoimmune diseases, such as SLE. However, much the PI3K/AKT and Janus kinases/signal transducer and activator of the underlying mechanism remains unknown, and further of transcription (JAK/STAT) pathways was also important in research is warranted. SLE CXCR4 dysregulation, which may add a piece to the puzzle. However, available evidence does not reveal the complicated underlying regulatory network, and more profound ACKNOWLEDGEMENTS in-depth studies are needed to better understand the initial self- This study was supported by grants from the National Natural Science Foundation of tolerance breakdown in GC and spontaneous autoreactive GC China (81788101, 81630044, 81601432, 81771763, 91542000), the Chinese Academy development. of Medical Science Innovation Fund for Medical Sciences (CIFMS2016-I2M-1-003, In conclusion, by locating the GC B cells correctly and 2017-I2M-1-008, 2017-I2M-3-011, 2016-I2M-1-008), and the Natural Science Founda- orchestrating B cells with compartment-speciﬁc helper cells (such tion of Beijing, China (7182129). as FDCs, TFH, macrophages, and reticular cells), chemokine receptors and their ligands, especially CXCR4/CXCL12 and ADDITIONAL INFORMATION CXCR5/CXCL13 pairs, have been indicated as indispensable in Competing interests: The authors declare no competing interests. normal GC reactions, whereas the dysregulation of these

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