Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice
Jing Zhao, … , Jonathan S. Bromberg, Reza Abdi
Jing Zhao, … , Jonathan S. Bromberg, Reza Abdi
Published December 15, 2022
Citation Information: J Clin Invest. 2022;132(24):e159672. https://doi.org/10.1172/JCI159672.
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Research Article Transplantation

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

Abstract

The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single-cell RNA sequencing of the LNs showed that anti-CD40L promotes a Madcam1+ FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node addressin (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79–anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79–anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance.

Authors

Jing Zhao, Sungwook Jung, Xiaofei Li, Lushen Li, Vivek Kasinath, Hengcheng Zhang, Said N. Movahedi, Ahmad Mardini, Gianmarco Sabiu, Yoonha Hwang, Vikas Saxena, Yang Song, Bing Ma, Sophie E. Acton, Pilhan Kim, Joren C. Madsen, Peter T. Sage, Stefan G. Tullius, George C. Tsokos, Jonathan S. Bromberg, Reza Abdi

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Figure 3

FRCs exert tolerogenic regulation on CD4+ T cells.

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FRCs exert tolerogenic regulation on CD4+ T cells. (A) Analysis of naive...
(A) Analysis of naive versus activated T cells with/without FRC coculture at different time points. Flow cytometric analysis demonstrating MFI of different T cell subtypes on days 0, 1, 2, and 3 following coculture with FRCs in complete T cell medium supplemented with anti-CD28 and anti-CD3. FRCs suppressed T cell proliferation and activation as analyzed by flow cytometry on days 0, 1, 2, and 3. (B) CD4+ T cell differentiation in the presence or absence of FRCs was analyzed along with different FRC and T cell ratios by flow cytometric assay on days 0, 3, and 5. In the presence of FRCs, a higher percentage of Foxp3-GFP+ cells and lower MFI of Th1, Th2, and Th17 cells were found. Two-way ANOVA with Sidak’s multiple comparisons test for multiple comparisons of each group. Data presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.