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Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction
Oscar Okwudiri Onyema, … , Elizabeth A. Jacobsen, Alexander Sasha Krupnick
Oscar Okwudiri Onyema, … , Elizabeth A. Jacobsen, Alexander Sasha Krupnick
Published June 6, 2019
Citation Information: JCI Insight. 2019;4(11):e128241. https://doi.org/10.1172/jci.insight.128241.
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Research Article Immunology Transplantation

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

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Abstract

Despite the accepted notion that granulocytes play a universally destructive role in organ and tissue grafts, it has been recently described that eosinophils can facilitate immunosuppression-mediated acceptance of murine lung allografts. The mechanism of eosinophil-mediated tolerance, or their role in regulating alloimmune responses in the absence of immunosuppression, remains unknown. Using lung transplants in a fully MHC-mismatched BALB/c (H2d) to C57BL/6 (H2b) strain combination, we demonstrate that eosinophils downregulate T cell–mediated immune responses and play a tolerogenic role even in the absence of immunosuppression. We further show that such downregulation depends on PD-L1/PD-1–mediated synapse formation between eosinophils and T cells. We also demonstrate that eosinophils suppress T lymphocyte responses through the inhibition of T cell receptor/CD3 (TCR/CD3) subunit association and signal transduction in an inducible NOS–dependent manner. Increasing local eosinophil concentration, through administration of intratracheal eotaxin and IL-5, can ameliorate alloimmune responses in the lung allograft. Thus, our data indicate that eosinophil mobilization may be utilized as a novel means of lung allograft–specific immunosuppression.

Authors

Oscar Okwudiri Onyema, Yizhan Guo, Bayan Mahgoub, Qing Wang, Amir Manafi, Zhongcheng Mei, Anirban Banerjee, Dongge Li, Mark H. Stoler, Melissa T. Zaidi, Adam G. Schrum, Daniel Kreisel, Andrew E. Gelman, Elizabeth A. Jacobsen, Alexander Sasha Krupnick

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Figure 1

Th1 polarization of the lung allograft.

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Th1 polarization of the lung allograft.
(A) Seven days after transplanta...
(A) Seven days after transplantation of BALB/c lung allograft to B6 recipient with or without CSB immunosuppression, the whole lung allograft (left) or flow cytometrically sorted lung-resident eosinophils (right) were phenotyped for Th1 or Th2 polarization using established markers. Comparison was made to E0 resting blood-resident eosinophils (white) or eosinophils polarized to the E1 (Th1) phenotype by overnight exposure to IFN-γ and TNF-α (yellow) or E2 (Th2) phenotype by overnight exposure to IL-33, IL-4, and GM-CSF (gray). Representative of 4 to 6 transplants per group, with Th2 analysis presented in Supplemental Figure 1. (B) Flow cytometric analysis of lung-resident eosinophils in BALB/c to B6 lung allografts with (blue) or without (red) CSB. Analysis of eosinophils from resting, untransplanted, B6 lungs shown as black line, while isotype control is shaded in gray. Representative of 3 to 5 separate transplants. (C) Histologic and flow cytometric analysis of BALB/c→iPhil transplants depleted of eosinophils with treatment by DT or saline control. Representative histologic section (top) and ISHLT A grade of rejection (bottom). Scale bar: 100 μm. (D) Total number of graft-resident T cells (top left) and a representative plot of flow cytometrically analyzed lung digest defining CD8+ T cells as CD90+CD8+ (top right). Total number of proliferating Ki-67+ T cells (middle left) and a representative plot of Ki-67+ CD8+ T cells (middle right). Relative proportion of effector T cells (defined as CD44hiCD62Llo) (bottom left) and a representative plot of CD8+ T cell effector differentiation (bottom right). All statistics performed by Mann-Whitney U test. *P < 0.05; **P < 0.01; nsP > 0.05.

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