CXCL12+ fibroblastic reticular cells in lymph nodes facilitate immune tolerance by regulating T cell–mediated alloimmunity
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
- Gianmarco Sabiu (ORCID: https://orcid.org/0000-0002-9514-1652)
- Pilhan Kim (ORCID: https://orcid.org/0000-0001-8388-1840)
- Vivek Kasinath (ORCID: https://orcid.org/0000-0001-6612-3466)
- Reza Abdi (ORCID: https://orcid.org/0000-0003-4789-5422)
- Jamil Azzi (ORCID: https://orcid.org/0000-0002-6909-4645)
- Lushen Li (ORCID: https://orcid.org/0000-0002-6701-7937)
- Sungwook Jung (ORCID: https://orcid.org/0000-0001-8012-190X)
- Andy Joe Seelam (ORCID: https://orcid.org/0000-0002-4211-5485)
- Jing Zhao (ORCID: https://orcid.org/0000-0002-4481-9080)
- Marina W. Shirkey
- Soyeon Ahn (ORCID: https://orcid.org/0000-0002-4955-523X)
- Yuta Yamamura (ORCID: https://orcid.org/0000-0003-3713-0733)
- Wenji Piao (ORCID: https://orcid.org/0000-0003-0005-3930)
- Xiaofei Li (ORCID: https://orcid.org/0000-0001-7661-0436)
- Song Yang (ORCID: https://orcid.org/0000-0003-1301-3030)
- Tianshu Zhang (ORCID: https://orcid.org/0000-0002-4053-2349)
- Long Wu (ORCID: https://orcid.org/0009-0007-5977-4747)
- Jonathan S. Bromberg
Institutions
- University of Maryland, Baltimore (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Korea Advanced Institute of Science and Technology (KR)
- SP Technology (South Korea) (KR)
- Korea Institute of Science and Technology (KR)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1172/jci182709
- Citations
- 2
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- Foundation for the National Institutes of Health
- American Heart Association
- American Society of Nephrology
- Takeda Science Foundation