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p40 Homodimers Stimulate Graft Dendritic Cells to Produce IL-15 Driving Endogenous Donor-Reactive Memory CD8 T Cell Activation within High-Risk Cardiac Allografts

H. Tsuda1, A. Valujskikh2, R. Fairchild3

1Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, 2The Cleveland Clinic Fdn, Cleveland, OH, 3Cleveland Clinic Foundation, Cleveland, OH

Meeting: 2022 American Transplant Congress

Abstract number: 628

Keywords: Co-stimulation, Heart/lung transplantation, Ischemia, T cell graft infiltration

Topic: Basic Science » Basic Science » 02 - Acute Rejection

Session Information

Session Name: Acute Rejection

Session Type: Poster Abstract

Date: Saturday, June 4, 2022

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

 Presentation Time: 5:30pm-7:00pm

Location: Hynes Halls C & D

*Purpose: Acute allograft injury occurring during the first 1-2 days post-transplant is mediated by graft infiltrating endogenous donor-reactive memory CD8 T cells and requires their proliferation within the graft. We reported that longer graft cold ischemic storage (CIS) times before transplant increases endogenous donor-reactive mCD8 T cell proliferation within complete MHC-mismatched murine cardiac allografts 1-2 days post-transplant and their expression of effector functions that mediate CTLA-4Ig-resistant graft rejection. The increased mCD8 T cell proliferation within such high-risk allografts requires p40 homodimers (p40HD) produced by graft DC.

*Methods: Here we investigated mechanisms underlying p40HD-induced endogenous mCD8 T cell proliferation within the heart allografts.

*Results: Purified CD8 T cells infiltrating allografts subjected to 8hr CIS expressed increased CD25 and CD122 mRNA levels on day 2 post-transplant with marked increases of IL-15, but not IL-2, protein in the graft. Blocking IL-15 signaling with anti-CD122 mAb inhibited early endogenous mCD8 T cell proliferation within high-risk allografts and prolonged graft survival in CTLA-4Ig conditioned recipients from day 18.5 with rat IgG treatment to day 53 median survival time (MST). Consistent with this, p40HD injection into recipients of low-risk allografts increased graft IL-15 mRNA and protein and the increased mCD8 T cell proliferation in the grafts was inhibited by anti-CD122, but not anti-CD25, mAb. To identify the allograft cells producing p40HD-induced IL-15, we transplanted hearts from diphtheria toxin (DT) receptor-CD11c transgenic mice. DT-mediated depletion of graft CD11c+ cells prior to transplant abrogated p40HD-induced IL-15 production and endogenous mCD8 T cell proliferation within low-risk allografts, implicating graft DC as the IL-15 producers. Use of IL15Rα-/- mice as donors of high ischemic allografts decreased early endogenous mCD8 T cell proliferation within grafts and extended graft survival in CTLA-4Ig conditioned recipients vs. wild-type allografts from day 33 to 69 MST.

*Conclusions: These results indicate that p40HD stimulate graft DCs to produce IL-15 that directly drives endogenous donor-reactive mCD8 T cell proliferation in high ischemic heart allografts to mediate CTLA-4Ig resistant rejection. This regulation of donor-reactive mCD8 T cell activation within allografts identifies novel targets to attenuate CTLA-4Ig resistant rejection mediated by these mT cells.

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To cite this abstract in AMA style:

Tsuda H, Valujskikh A, Fairchild R. p40 Homodimers Stimulate Graft Dendritic Cells to Produce IL-15 Driving Endogenous Donor-Reactive Memory CD8 T Cell Activation within High-Risk Cardiac Allografts [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/p40-homodimers-stimulate-graft-dendritic-cells-to-produce-il-15-driving-endogenous-donor-reactive-memory-cd8-t-cell-activation-within-high-risk-cardiac-allografts/. Accessed May 25, 2025.

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