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T Cell Overexpression of PD-1 Increases Treg Suppressive Function via an ICOS-Dependent Mechanism

T. J. Borges1, N. Murakami2, I. T. Lape1, R. B. Gassen1, K. Liu1, L. V. Riella1

1Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, 2Transplantation Research Center, Brigham and Women's Hospital, Boston, MA

Meeting: 2022 American Transplant Congress

Abstract number: 380

Keywords: T cell activation, T helper cells, Tolerance

Topic: Basic Science » Basic Science » 10 - Treg/Other Regulatory Cell/Tolerance

Session Information

Session Name: Immunoregulation and Tolerance

Session Type: Rapid Fire Oral Abstract

Date: Monday, June 6, 2022

Session Time: 5:30pm-7:00pm

 Presentation Time: 5:50pm-6:00pm

Location: Hynes Room 302

*Purpose: The PD-1: PD-L1 signaling has inhibitory properties and is a potential therapeutic target in transplantation. We have previously demonstrated that overexpression of PD-1 on T cells (PD-1 Tg) when combined with costimulation blockade (CTLA-4-Ig), promotes allograft tolerance in a fully MHC-mismatched cardiac transplant model. Thus, the modulation of PD-1 expression is a promising therapeutic target for long-term allograft acceptance. In this study, we aim to identify the mechanisms underlying the long-term graft survival in PD-1 Tg mice.

*Methods: BALB/c (H-2d) hearts were transplanted into WT or PD-1 Tg B6 (H-2b) mice treated with a single dose of CTLA-4-Ig. In some experiments, Tregs were depleted by treating animals with an anti-CD25 antibody on days -7 and -1. We assessed ICOS potential role in vivo by treating animals with an anti-ICOS blocking antibody or isotype control on days 0, 2, 4 and 6. Animals were euthanized at POD21 for mechanistic analyses. Graft, spleen and draining lymph nodes were analyzed by flow cytometry and ELISPOT. Flow-sorted PD-1 Tg Tregs (CD4+Foxp3-GFP+) were further analyzed using an RT-PCR array and an in vitro suppression assay. We analyzed over 90 functional markers on the Tregs.

*Results: We identified that Tregs from PD-1 Tg mice were required for tolerance induction (MST=89 days vs >100 days, p=0.0174). PD-1 Tg Tregs had higher expression of ICOS at both mRNA and protein levels when compared to WT Tregs. Prolongation of allograft survival in PD-1 Tg recipients was abrogated upon ICOS blockade, indicating a critical role for ICOS in the tolerance induction (MST: 23 vs >100 days, p=0.0133). Compared to WT Tregs, intragraft and splenic Tregs from PD-1 Tg recipients had a higher expression of IL-10 (p=0.0207) and LAP (p=0.0374), which was decreased by anti-ICOS treatment (p=0.0008 and p=0.0421) expression at day 21 post-transplant. We verified by ELISPOT that the increased IL-10 production in PD-1 Tg recipients (p<0.0001) was allo-specific, and it was inhibited by ICOS blockade (p=0.0009). Moreover, we flow-sorted Tregs from PD-1 Tg heart recipients had a superior ability to inhibit T cell proliferation (p=0.0445). This effect was abrogated by the anti-ICOS treatment (p=0.0145). Importantly, ICOS blockade had minimal effects on effector T cell responses, suggesting that the anti-ICOS treatment has a dominant inhibitory effect on Treg suppressive function.

*Conclusions: In sum, our data suggest that the PD-L1:PD-1 pathway is a promising target in transplantation, especially in synergy with costimulation blockade. PD-1 overexpression on T cells leads to an increase of ICOS expression on Tregs and its superior suppressive functions are dependent on this molecule.

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To cite this abstract in AMA style:

Borges TJ, Murakami N, Lape IT, Gassen RB, Liu K, Riella LV. T Cell Overexpression of PD-1 Increases Treg Suppressive Function via an ICOS-Dependent Mechanism [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/t-cell-overexpression-of-pd-1-increases-treg-suppressive-function-via-an-icos-dependent-mechanism/. Accessed May 9, 2025.

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