3 years ago

Inhibition of T Cell Alloreactivity by Bronchial Epithelium Is Impaired in Lung Transplant Recipients, Through Pathways Involving TGF-β, IL-10 and HLA-G

Danel, Claire, Castier, Yves, Carosella, Edgardo, Rouas-Freiss, Nathalie, Bunel, Vincent, Mordant, Pierre, Thabut, Gabriel, Dupin, Clairelyne, Létuvé, Séverine, Pretolani, Marina, Mal, Hervé, Lhuillier, Elodie, Brugière, Olivier, Schilte, Clémentine
imageBackground: Bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx) results from bronchial epithelial cell (BECs) damages, thought to be orchestrated by T cells primed by antigen-presenting cell presenting alloantigens. In this cell cross-talk, BECs are also suspected to play a pivotal immunosuppressive role in T cell alloreactivity. We studied the immunomodulating role of BECs in a human ex vivo model of allogeneic T cell response, both in healthy subjects and LTx recipients. Methods: BECs from 35 LTx recipients (n = 22 stable, n = 13 BOS) and healthy controls (n = 25) were cultured as primary cell cultures. Their inhibitory capacities through the involvement of tolerogenic molecules (HLA-G, TGF-β, and IL-10) were tested on a mixed lymphocyte reaction between antigen-presenting cells and recipient T cells. Results: Control BECs inhibited T cell alloproliferation by a mean of 53 ± 7%. This inhibitory effect of BECs was significantly reduced in the stable LTx group (24 ± 8%, P = 0.009), but not in the BOS TxP group (53 ± 10%, P = 0.97). Neutralization of HLA-G, TGF-β, and IL-10 partially restored T cell alloproliferation, arguing for their involvement in the immunosuppressive effect of BECs. BECs culture supernatant from stable LTx patients with impaired BEC properties showed a skewed Th2-type secretion profile (high IL-4/IFN-γ ratio). Conclusions: The inhibitory properties of BECs are dysregulated in stable LTx recipients, which could suggest their instrumental role in the initiation of BOS process and potential targeted therapies.
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