CXCL12+ fibroblastic reticular cells in lymph nodes facilitate immune tolerance by regulating T cell–mediated alloimmunity
Yuta Yamamura, Gianmarco Sabiu, Jing Zhao, Sungwook Jung, Andy J. Seelam, Xiaofei Li, Yang Song, Marina W. Shirkey, Lushen Li, Wenji Piao, Long Wu, Tianshu Zhang, Soyeon Ahn, Pilhan Kim, Vivek Kasinath, Jamil R. Azzi, Jonathan S. Bromberg, Reza Abdi
Yuta Yamamura, Gianmarco Sabiu, Jing Zhao, Sungwook Jung, Andy J. Seelam, Xiaofei Li, Yang Song, Marina W. Shirkey, Lushen Li, Wenji Piao, Long Wu, Tianshu Zhang, Soyeon Ahn, Pilhan Kim, Vivek Kasinath, Jamil R. Azzi, Jonathan S. Bromberg, Reza Abdi
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Research Article Immunology

CXCL12+ fibroblastic reticular cells in lymph nodes facilitate immune tolerance by regulating T cell–mediated alloimmunity

Abstract

Fibroblastic reticular cells (FRCs) are the master regulators of the lymph node (LN) microenvironment. However, the role of specific FRC subsets in controlling alloimmune responses remains to be studied. Single-cell RNA sequencing (scRNA-Seq) of naive and draining LNs (DLNs) of heart-transplanted mice and human LNs revealed a specific subset of CXCL12hi FRCs that expressed high levels of lymphotoxin-β receptor (LTβR) and are enriched in the expression of immunoregulatory genes. CXCL12hi FRCs had high expression of CCL19, CCL21, indoleamine 2,3-dioxygenase (IDO), IL-10, and TGF-β1. Adoptive transfer of ex vivo–expanded FRCs resulted in their homing to LNs and induced immunosuppressive environments in DLNs to promote heart allograft acceptance. Genetic deletion of LTβR and Cxcl12 in FRCs increased alloreactivity, abrogating the effect of costimulatory blockade in prolonging heart allograft survival. As compared with WT recipients, CXCL12+ FRC–deficient recipients exhibited increased differentiation of CD4+ T cells into Th1 cells. Nano delivery of CXCL12 to DLNs improved allograft survival in heart-transplanted mice. Our study highlights the importance of DLN CXCL12hi FRCs in promoting transplant tolerance.

Authors

Yuta Yamamura, Gianmarco Sabiu, Jing Zhao, Sungwook Jung, Andy J. Seelam, Xiaofei Li, Yang Song, Marina W. Shirkey, Lushen Li, Wenji Piao, Long Wu, Tianshu Zhang, Soyeon Ahn, Pilhan Kim, Vivek Kasinath, Jamil R. Azzi, Jonathan S. Bromberg, Reza Abdi

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Figure 3

CXCL12hi FRC subsets enriched for genes for T cell migration.

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CXCL12hi FRC subsets enriched for genes for T cell migration. (A) Unsupe...
(A) Unsupervised clustering of FRC subset clusters visualized with UMAP in LNSCs from naive LNs. (B) Violin plots of Ltbr and Cxcl12 expression among FRC subset clusters in naive LNs. (C) Violin plots of Ltbr and Cxcl12 expression in total FRCs from naive LNs. (D) UMAP of SC populations in naive LNs and DLNs, highlighting Cxcl12 expression on MedRC, TRC, and PRC subsets. (E) Violin plots of Cxcl12 expression in FRC subsets from naive LNs and DLNs. (F) Volcano plot comparing CXCL12hi and CXCL12lo FRCs in mouse LNSCs from heart transplanted recipients with anti-CD40L treatment. (G) Top 20 overrepresented ontology pathways based on DEGs in mouse LNSCs. (H) Volcano plot comparing CXCL12hi and CXCL12lo FRCs in human LNSCs. (I) Top 20 overrepresented ontology pathways in human LNSCs. Common genes shared between mouse and human are highlighted with bold letters surrounded by squares (F and H). Ontology pathways related to chemotaxis and migration are highlighted with bold letters surrounded by squares (G and I). HTx, heart transplantation.