Fibroblastic reticular cells orchestrate long-term graft survival following recipient treatment with CD40 ligand–targeted costimulatory blockade
Robert L. Fairchild
Robert L. Fairchild
Published December 15, 2022
Citation Information: J Clin Invest. 2022;132(24):e165174. https://doi.org/10.1172/JCI165174.
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Commentary

Fibroblastic reticular cells orchestrate long-term graft survival following recipient treatment with CD40 ligand–targeted costimulatory blockade

Abstract

Fibroblastic reticular cells (FRCs) maintain the architecture of secondary lymphoid organs, which optimize interactions between antigen-presenting dendritic cells and reactive naive T cells. In this issue of the JCI, Zhao, Jung, and colleagues investigated CD4+FoxP3+ regulatory T cell development and long-term heart allograft survival in recipients treated with peritransplant costimulatory blockade to inhibit CD40/CD40 ligand (CD40L) signaling. Treatment with an anti-CD40L monoclonal antibody (mAb) increased the lymph node (LN) population of Madcam1+ FRCs and altered their transcription profile to express immunoregulatory mediators. Administration of nanoparticles, containing the anti-CD40L mAb and a targeting antibody against high endothelial venules, delivered the treatment into LNs of allograft recipients. Direct LN delivery of the costimulatory blockade allowed decreased dosing and increased the efficacy in extending graft survival. The results provide insights into mechanisms by which FRCs can promote donor-reactive tolerance, and establish a strategy for administering costimulation-blocking reagents that circumvent systemic effects and improve allograft outcomes.

Authors

Robert L. Fairchild

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Figure 1

Fibroblastic reticular cells organize alloantigen-reactive effector and regulatory CD4+ T cell responses in the lymph node.

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Fibroblastic reticular cells organize alloantigen-reactive effector and ...
(A) Following allogeneic heart transplantation, fibroblastic reticular cells (FRCs) in the recipient lymph nodes organize interactions between dendritic cells (DCs) entering the lymph nodes through the afferent lymphatics and naive CD4+ T cells entering through the high endothelial venules (HEVs). CD4+ T cells reactive to graft allogeneic class II MHC molecules and receiving costimulatory signals through engagement of CD40L with DC-expressed CD40 are activated to clonally proliferate and differentiate into effector T cells that will participate in rejection of the allograft. (B) Peritransplant treatment with anti-CD40L mAb costimulatory blockade inhibits delivery of the DC CD40-costimulatory signals to the reactive T cells and diverts their differentiation to regulatory cells (Tregs) that inhibit the allograft-reactive immune response and promote long-term allograft acceptance. Zhao and colleagues show that administration of nanoparticles encapsulating the anti-CD40L mAb and conjugated with MECA-79, a mAb directing the beads to and through the HEV, increases the efficacy of the costimulatory blockade treatment in promoting the long-term survival of the allografts.