Lymph node fibroblastic reticular cells preserve a tolerogenic niche in allograft transplantation through laminin α4
Lushen Li, Marina W. Shirkey, Tianshu Zhang, Wenji Piao, Xiaofei Li, Jing Zhao, Zhongcheng Mei, Yizhan Guo, Vikas Saxena, Allison Kensiski, Samuel J. Gavzy, Yang Song, Bing Ma, Jing Wu, Yanbao Xiong, Long Wu, Xiaoxuan Fan, Holly Roussey, Meng Li, Alexæander S. Krupnick, Reza Abdi, Jonathan S. Bromberg
Lushen Li, Marina W. Shirkey, Tianshu Zhang, Wenji Piao, Xiaofei Li, Jing Zhao, Zhongcheng Mei, Yizhan Guo, Vikas Saxena, Allison Kensiski, Samuel J. Gavzy, Yang Song, Bing Ma, Jing Wu, Yanbao Xiong, Long Wu, Xiaoxuan Fan, Holly Roussey, Meng Li, Alexæander S. Krupnick, Reza Abdi, Jonathan S. Bromberg
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Research Article Cell biology

Lymph node fibroblastic reticular cells preserve a tolerogenic niche in allograft transplantation through laminin α4

Abstract

Lymph node (LN) fibroblastic reticular cells (FRCs) define LN niches and regulate lymphocyte homeostasis through producing diverse extracellular matrix (ECM) components. We examined the role of ECM laminin α4 (Lama4) using FRC-Lama4 conditional KO Pdgfrb-Cre–/– × Lama4fl/fl mice. Single-cell RNA-sequencing (scRNA-Seq) data showed the promoter gene Pdgfrb was exclusively expressed in FRCs. Depleting FRC-Lama4 reduced Tregs and dendritic cells, decreased high endothelial venules, impaired the conduit system, and downregulated T cell survival factors in LNs. FRC-Lama4 depletion impaired the homing of lymphocytes to LNs in homeostasis and after allografting. Alloantigen-specific T cells proliferated, were activated to greater degrees in LNs lacking FRC-Lama4, and were more prone to differentiate into effector phenotypes relative to the Treg phenotype. In murine cardiac transplantation, tolerogenic immunosuppression was not effective in FRC-Lama4 recipients, which produced more alloantibodies than WT. After lung transplantation, FRC-Lama4–KO mice had more severe graft rejection with fewer Tregs in their LNs. Overall, FRC-Lama4 critically contributes to a tolerogenic LN niche by supporting T cell migration, constraining T cell activation and proliferation, and promoting Treg differentiation. Hence, it serves as a therapeutic target for immunoengineering.

Authors

Lushen Li, Marina W. Shirkey, Tianshu Zhang, Wenji Piao, Xiaofei Li, Jing Zhao, Zhongcheng Mei, Yizhan Guo, Vikas Saxena, Allison Kensiski, Samuel J. Gavzy, Yang Song, Bing Ma, Jing Wu, Yanbao Xiong, Long Wu, Xiaoxuan Fan, Holly Roussey, Meng Li, Alexæander S. Krupnick, Reza Abdi, Jonathan S. Bromberg

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Figure 8

FRC-Lama4 regulates Treg versus T effector balance in cardiac transplants.

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FRC-Lama4 regulates Treg versus T effector balance in cardiac transplant...
(A) Schematic of cardiac transplantation with immunosuppression and transfer of alloantigen-specific, TCR Tg TEa CD4+ T cells and 2C CD8+ T cells. On day 0, CFSE-stained TEa plus 2C cells (2 × 106 each) with or without 250 μg anti-CD40L injected i.v. to WT or FRC-Lama4–KO recipients. LNs harvested on day 5 to assess TEa and 2C cell differentiation. (B) Representative gating of TEa CD4+ T cells and differentiation to Foxp3+Treg, T-bet+Th1, GATA3+Th2, and RORγt+Th17 cells from Foxp3– TEa cells. (C) Data summary of TEa differentiation and ratio of Treg/T effector cells (D) Gating of 2C cells and data summary of 2C differentiation (gating of T-bet+Tc1, GATA3+Tc2, and RORγt+Tc17 cells same as TEa effector cells in B). Data are representative of 3 independent experiments; 3 mice/group. Two-way ANOVA with multiple comparisons test for multiple comparisons of each group. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001. P < 0.05 was considered significant.