TY - JOUR
T1 - Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction
AU - Onyema, Oscar Okwudiri
AU - Guo, Yizhan
AU - Mahgoub, Bayan
AU - Wang, Qing
AU - Manafi, Amir
AU - Mei, Zhongcheng
AU - Banerjee, Anirban
AU - Li, Dongge
AU - Stoler, Mark H.
AU - Zaidi, Melissa T.
AU - Schrum, Adam G.
AU - Kreisel, Daniel
AU - Gelman, Andrew E.
AU - Jacobsen, Elizabeth A.
AU - Krupnick, Alexander Sasha
N1 - Publisher Copyright:
Copyright: © 2019 American Society for Clinical Investigation
PY - 2019/6/6
Y1 - 2019/6/6
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.128241
DO - 10.1172/jci.insight.128241
M3 - Article
C2 - 31167966
AN - SCOPUS:85070659122
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 11
M1 - e128241
ER -