Yoshihiro NagaseMakoto KodamaEriko AimonoKohei NakamuraReika TakamatsuKeiko AbeTakuma YoshimuraTatsuyuki ChiyodaWataru YamagamiHiroshi Nishihara
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Abstract Immune checkpoint inhibitor (ICI) therapy has been successfully applied to various cancers; however, not all patients respond to ICI therapy. Tumors with an immune‐activated environment are highly responsive to ICIs. To identify the cells and molecules essential to the formation of an immune‐activated cancer microenvironment, we focused on the tertiary lymphoid structure (TLS) and performed histological and genomic analyses using endometrial cancer material. In the high immunogenic group, numerous TLSs were observed, and CXCL9 and CXCL13 expression was markedly increased. CXCL9‐positive antigen‐presenting and CXCL13‐positive follicular dendritic cells were distributed in the T‐ and B‐cell zones of TLSs, respectively. A group of molecules whose expression was upregulated along with CXCL9 and CXCL13 expression was strongly associated with cellular immunity. These results suggest that CXCL9‐expressing antigen‐presenting cells and CXCL13‐expressing follicular dendritic cells coordinately shape the immune‐activated microenvironment through TLS formation. The current findings will contribute to a better understanding of the mechanisms underlying the activated cancer immune microenvironment, thereby advancing the field of precision cancer medicine.Keywords:
CXCL13
Follicular dendritic cells
CXCL9
Angioimmunoblastic T-cell lymphoma (AITL) is considered to originate from follicular helper T (TFH) cells. Currently, neoplastic cells in AITL are considered to express CXCL13 as a tumor marker. However, the identification of CXCL13+ cells remains unclear in terms of whether they are neoplastic cells (or TFH cells) or follicular dendritic cells (FDCs) in both AITL and normal germinal centers. Therefore, the exact identification of CXCL13+ cells was performed using 33 cases of AITL and normal germinal centers. Single-labeling immunohistochemistry and double-labeling immunofluorescent microscopy first confirmed that CXCL13 was expressed mainly in FDCs in the normal germinal centers. In 28 of 33 AITL cases, CXCL13 was expressed mainly in FDCs as a meshwork pattern, which was associated with CXCL13+ neoplastic cells. In the other five cases, CXCL13 was expressed mainly in neoplastic cells, which were densely distributed in and around the FDC meshwork. These findings indicate the abundance of CXCL13+ cells in the FDC meshwork irrespective of the cell type. Triple-labeling immunofluorescent microscopy showed that the CXCL13+ FDC meshwork in AITL harbored both neoplastic cells and B cells. CXCR5, the cognate receptor of CXCL13, was expressed in neoplastic cells in AITL. The present study suggests that neoplastic cells in AITL preserve a certain level of TFH-cell function since neoplastic cells and B cells are closely enmeshed in the CXCL13+ cell-rich FDC meshwork in a similar way as in normal germinal centers. [J Clin Exp Hematop 55(2) : 61-69, 2015]
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Angioimmunoblastic T-cell lymphoma
Follicular dendritic cells
CXCR5
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Follicular dendritic cells (FDCs), the best defined stromal cell subset within lymphoid follicles, play a critical role in presenting intact antigen to B lymphocytes. The discovery that many follicular stromal cells make B-lymphocyte chemoattractant (BLC), a CXC chemokine that attracts CXCR5+ cells, provides a basis for understanding how motile B cells come into contact with stationary FDCs. Here we review our work on BLC and discuss properties of BLC-expressing follicular stromal cells. We also review the properties of primary follicle and germinal center FDCs and suggest a model of FDC development that incorporates information about BLC expression. Finally, we consider how antigen recognition causes T and B lymphocytes to undergo changes in chemokine responsiveness that may help direct their movements into, or out of, lymphoid follicles.
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CXCR5
Follicular dendritic cells
Homing (biology)
Lymphocyte homing receptor
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Follicular dendritic cells
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Follicular dendritic cells (FDCs) retain and display opsonized antigens in primary follicles and germinal centers (GCs). However, their roles beyond antigen presentation have been incompletely defined. In this study, we tested the impact of selective FDC ablation on short-term follicle and GC function. Within 2 d of FDC ablation, primary follicles lost their homogeneity and became disorganized bands of cells around T zones. These B cell areas retained CXCL13-expressing stromal cells but often exhibited inappropriate ER-TR7 and CCL21 expression. Ablation of GC FDCs led to the disappearance of GCs. When B cell death was prevented using a Bcl2 transgene, FDC ablation led to splenic GC B cell dispersal. Mesenteric lymph node GCs were more resistant but became dispersed when sphingosine-1-phosphate receptor-2 was also removed. These experiments indicate that FDCs help maintain primary follicles as a B cell exclusive niche and define a critical role for FDCs in cell retention within GCs.
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Abstract Background and Aims Chemokines are deeply involved in the process of inflammatory and immune responses. Interferon-γ-inducible chemokines C-X-C motif chemokine 9 and 10 (CXCL9 and CXCL10) are significantly associated with Th1 cells and monocytes and rise rapidly during early episode of renal allograft rejection and various infectious diseases. CXCL13 is one of the most potent B cells and T follicular helper (Tfh) cells chemoattractants when acts through its cognate receptor CXCR5. Recent work of CXCL13 indicated a critical immune regulatory role in both multiple infectious diseases and kidney transplantation. Additionally, C-C motif chemokine 2 (CCL2) is shown to be is critical for chronic kidney diseases. The aim of this study was to identify the predictive role of serum CXCL9, CXCL10, CXCL13 or CCL2 on kidney posttransplant infection. Method 95 kidney transplant recipients (KTRs) were enrolled in this study. 31 recipients experienced at least once infection episodes within the first posttransplant 12 months and 64 KTRs did not experience any infection episode during the follow-up period. Serum CXCL9, CXCL10, CXCL13 and CCL2 at the time points of pre-transplantation and post-transplant 30 days (POD 30) were analyzed with Bio-Plex® suspension array system. Results It was found that serum level of POD 30 CXCL9 and POD 30 CXCL13 was associated with infection within one year after transplantation (P=0.021, P=0.002, respectively, shown in Figure 1). The serum level of CXCL9 and CXCL13 before surgery, the serum level of CCL2 and CXCL10 before and after surgery were not associated with infection within posttransplant one year (P>0.05, shown in Figure 1). The combination of POD 30 CXCL9 plus POD 30 CXCL13 provided the best results with AUC of 0.721 (95%CI, 0.591-0.852), sensitivity of 71.4% and specificity of 68.5% at the optimal cut-off value of 52.72 pg/ml (shown in Figure 2). Conclusion Chemokines CXCL9 and CXCL13 as important chemokines could be used to predict the occurrence of infection within posttransplant one year in kidney transplant recipients.
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Abstract Secondary lymphoid organs (SLOs) are integral in generating an effective adaptive immune response. Homing of cells to SLOs is a result of homeostatic chemokines, such as CXCL13. CXCL13, the ligand for CXCR5, is responsible for the recruitment of germinal center cells including B cells, T follicular helper (Tfh) cells and follicular dendritic cells (FDCs). Recently, CXCL13 has been reported in the lungs of mice following infection with Mycobacterium tuberculosis (Mtb). We found CXCL13 to be localized within the granuloma in both mice and human lungs as early as day 22 post infection in mice. In addition, we found Tfh cells, B cells, and FDCs localized within the granuloma of mice and humans. Recruitment of Tfh cells was seen in the draining lymph nodes by day 15 with accumulation in the lung by day 21 in Mtb infected mice. Infiltration of Tfh cells in the lung coincided with an increase in mRNA for known Tfh factors such as ICOS, BCL-6, IL-6 and IL-21, which followed upregulation of CXCL13 at day 18. Interestingly, another CXCR5+ population infiltrated the lung prior to accumulation of Tfh cells. These cells accumulate at day 12 and express surface markers suggestive of a monocyte lineage. Further, CXCR5-/- mice are more susceptible to Mtb infection by day 21. Our data suggest that the Mtb granuloma may function as an ectopic lymphoid organ, which may require involvement of CXCR5+ cells to elicit protective immunity.
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Follicular dendritic cells
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The homeostatic chemokine CXCL13 is preferentially produced in B-follicles and is crucial in the lymphoid organ development by attracting B-lymphocytes that express its selective receptor CXCR5. Follicular dendritic cells (FDCs) have been identified as the main cellular source of this chemokine in lymphoid organs. Recently, genome-wide approaches have suggested follicular CD4 T-helper cells (T(H)F) as additional CXCL13 producers in the germinal centre and the neoplastic counterpart of T(H)F (CD4+ tumour T-cells in angioimmunoblastic T-cell lymphoma) retains the capability of producing this chemokine. In contrast, no data are available on CXCL13 expression on FDC sarcoma (FDC-S) cells. By using multiple approaches, we investigated the expression of CXCL13 at mRNA and protein level in reactive and neoplastic FDCs. In reactive lymph nodes and tonsils, CXCL13 protein is mainly expressed by a subset of FDCs in B-cell follicles. CXCL13 is maintained during FDC transformation, since both dysplastic FDCs from 13 cases of Castleman's disease and neoplastic FDCs from ten cases of FDC-S strongly and diffusely express this chemokine. This observation was confirmed at mRNA level by using RT-PCR and in situ hybridization. Of note, no CXCL13 reactivity was observed in a cohort of epithelial and mesenchymal neoplasms potentially mimicking FDC-S. FDC-S are commonly associated with a dense intratumoural inflammatory infiltrate and immunohistochemistry showed that these lymphocytes express the CXCL13 receptor CXCR5 and are mainly of mantle zone B-cell derivation (IgD+ and TCL1+). In conclusion, this study demonstrates that CXCL13 is produced by dysplastic and neoplastic FDCs and can be instrumental in recruiting intratumoural CXCR5+ lymphocytes. In addition to the potential biological relevance of this expression, the use of reagents directed against CXCL13 can be useful to properly identify the origin of spindle cell and epithelioid neoplasms.
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Follicular dendritic cells
CXCR5
Follicular lymphoma
Mantle zone
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Background and Objective: B lymphocyte is the dominant infiltrating cell type in periodontitis lesions. CXCL13, produced by follicular dendritic cells, endothelial cells and fibroblasts, is crucial for B‐cell trafficking. An association between chronic inflammation and lymphoid organogenesis has been reported in infection and in autoimmune responses, in which T‐cell/B‐cell follicles with a follicular dendritic cell network are formed. The aim of this study was to examine CXCL13 expression and follicular dendritic cell distribution in relation to B‐cell infiltration in chronic inflammatory periodontal lesions. Material and Methods: Fifty‐eight gingival tissue biopsies from patients with periodontitis and 25 samples from subjects with gingivitis were analyzed. Gene expression for CXCL13 and for the CD21 long isoform was analyzed using the reverse transcription–polymerase chain reaction. Immunohistochemical analysis was performed using antibodies to CXCL13, CXCR5, follicular dendritic cells, CD3 and CD19 on serial cryostat sections. Results: mRNA for CXCL13 was expressed in both periodontitis and gingivitis tissues. The number of CXCL13 + cells was significantly higher in periodontitis than in gingivitis in connective tissues subjacent to the pocket epithelium and positively correlated with the number of CD19 + cells. CXCL13 + cells were distributed in B‐cell‐dominant areas both with and without follicular dendritic cells. Although obvious reticular networks of follicular dendritic cells were not found in periodontitis and gingivitis, the accumulation of follicular dendritic cells in B‐cell‐dominant areas in periodontitis was observed in some patients. Conclusion: These findings suggested that CXCL13 and follicular dendritic cells were involved in B‐cell recruitment to, and B‐cell distribution in, chronic inflammatory periodontal lesions.
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Tertiary lymphoid organs (TLOs) are aggregates of B and T cells formed in response to chronic immune responses. TLOs are the result of lymphoid neogenesis and are formed via production of lymphoid-organizing chemokines (CXCL13, CCL19 and CCL21), in response to signaling from lymphotoxin α (LTα) via TNFR1, TNFR2 and LTR. Stromal cells and antigen presenting cells (APCs), i.e. dendritic cells (DCs), secrete lymphoid chemokines, which attract B cells, T cells and DCs via CCR7 (receptor for CCL19/21) and CXCR5 (receptor for CXCL13). Lymphoid follicles are frequently found in the peripheral lungs of patients with Chronic Obstructive Pulmonary Disease (COPD). Whether they are the result of lymphoid neogenesis remains elusive. Here, we have identified 18 patients with COPD and lymphoid follicles and used immunohistochemistry to analyze the expression of LTa and lymphoid chemokines. Flow cytometry was applied to study expression of their receptors. LTα is abundantly expressed by alveolar macrophages and lung stromal cells and CXCL13 is strongly expressed inside the follicles. HLA-DR+ve cells (APCs), but not CD45-ve stromal cells, strongly express TNFR1 (43% of APCs), TNFR2 (47%) and LTR (38%). CXCR5 is expressed by B cells (96% of B cells), DCs (74% of DCs) and T cells (24% of T cells). CCL19, CCL21 and CCR7 are rarely expressed. In conclusion, molecular mechanisms underlying TLO formation might be involved in lymphoid follicle formation in COPD as follows: stromal cells and macrophages secrete LTa, which induces CXCL13 production by lung APCs, driving the accumulation of CXCR5 bearing B cells, T cells and DCs to sites of TLO. Funded by the Hellenic Thoracic Society.
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Follicular dendritic cells
CXCR5
CCL19
CCL20
High endothelial venules
CXCL16
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Abstract A unique feature in inflammatory tissue of rheumatoid arthritis (RA) is the formation of ectopic lymphoid aggregates with germinal center (GC)-like structures that can be considered to contribute to the pathogenesis of RA, because local production of the autoantibody, rheumatoid factor, is thought to be a causative factor in tissue damage. However, the factors governing the formation of GC in RA are presently unknown. To begin to address this, the expression of B cell attracting chemokine (BCA-1) (CXCL13), a potent chemoattractant of B cells, was examined in the synovium of patients with RA or with osteoarthritis (OA). Expression of BCA-1 mRNA was detected in all RA samples, but in only one of five OA samples. Lymphoid follicles were observed in four of seven RA samples and in two of eight OA samples, and in most of them BCA-1 protein was detected in GC. BCA-1 was not detected in tissues lacking lymphoid follicles. Notably, BCA-1 was detected predominantly in follicular dendritic cells in GC. CD20-positive B cells were aggregated in regions of BCA-1 expression, but not T cells or macrophages. These data suggest that BCA-1 produced by follicular dendritic cells may attract B cells and contribute to the formation of GC-like structures in chronic arthritis.
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Follicular dendritic cells
Ectopic expression
Rheumatoid factor
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