INTRODUCTION: We recently reported that endogenous memory CD8+ T cells infiltrate MHC-mismatched cardiac allografts and are activated to proliferate and produce IFN-Γ in response to donor class I MHC molecules within 24 hours after reperfusion in mice. This infiltration is inhibited by treating recipients with anti-LFA-1 mAb on days -1 and 0 but not on days 3 and 4. The current studies were conducted to test the ability of allograft infiltrating endogenous CD8 T cells to mediate rejection.
METHODS: Syngeneic or MHC-mismatched A/J (H-2a) hearts were transplanted into C57BL/6 (H-2b) recipients. Anti-LFA-1 mAb (250 ug) was given on days 3 and 4 post-transplant. Grafts were harvested on day 2 or 7 post-transplant and mRNA encoding inflammatory cytokines was measured by qRT-PCR from total graft homogenates. CD4 and CD8 T cell, macrophage, and neutrophil infiltration was assessed by flow cytometry and immunohistochemistry. Donor-specific T cells producing IFN-Γ in the recipient spleen and in the graft were detected by ELISPOT assay.
RESULTS: Allografts from recipients given anti-LFA-1 mAb on days 3 and 4 were not rejected until day 14-18 post-transplant (vs. day 8 in control Ig treated recipients) and rejection correlated with delayed priming of donor-reactive CD8 T cells producing IFN-g in the spleen. However, allografts from the anti-LFA-1 mAb treated recipients had marked increases in numbers of infiltrating CD8 T cells on day 7 post-transplant when compared to rejecting allografts from control Ig treated recipients. Allografts from the anti-LFA-1 treated recipients had low-absent numbers of infiltrating neutrophils. The CD8 T cells infiltrating allografts in anti-LFA-1 mAb treated recipients took up BrdU on day 7 indicating their proliferation, did not express increased levels of the exhaustion marker LAG-3 when compared to infiltrating CD8 T cells in control Ig treated recipients, but had a 60% decrease in donor-reactive CD8 cells producing IFN-g.
CONCLUSIONS: These data indicate that endogenous memory CD8 T cells infiltrating MHC-mismatched cardiac allografts early after reperfusion are activated to proliferate within the allograft but do not express sufficient effector functions to recruit neutrophils into the allograft and mediate the overt graft injury causing rejection.
To cite this abstract in AMA style:Iida S, Setoguchi K, Hattori Y, Su C, III WBaldwin, Tanabe K, Fairchild R. Endogenous Memory CD8 T Cells Are Activated To Proliferate and Express Effector Functions within Cardiac Allografts without Mediating Rejection [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/endogenous-memory-cd8-t-cells-are-activated-to-proliferate-and-express-effector-functions-within-cardiac-allografts-without-mediating-rejection/. Accessed July 4, 2020.
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