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



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.



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).



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.
1 INSERM UMR1152, Paris Diderot University, Paris, France. 2 CEA, IMETI, Hemato-immunology research department, Saint-Louis Hospital, Paris, France. 3 Paris Diderot University, Sorbonne Paris Cité, IUH, Paris, France. 4 Pneumology B and Lung Transplantation Department, Bichat Hospital, Paris, France. 5 Laboratory of Excellence INFLAMEX, Université Sorbonne Paris-Cité, Paris, France. 6 Département Hospitalo-Universitaire FIRE, Paris, France. 7 Pathology Department, Bichat hospital, Paris, France. 8 Thoracic Surgery Department, Bichat hospital, Paris, France. 9 Anesthesia Intensive Care, Bichat Hospital, Paris, France.
Clairelyne
C
Dupin
Elodie
E
Lhuillier
Séverine
S
Létuvé
Marina
M
Pretolani
Gabriel
G
Thabut
Hervé
H
Mal
Edgardo
E
Carosella
Clémentine
C
Schilte
Pierre
P
Mordant
Yves
Y
Castier
Vincent
V
Bunel
Claire
C
Danel
Nathalie
N
Rouas-Freiss
Olivier
O
Brugière
D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D059951:HLA-G Antigens / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018928:Immunity, Mucosal; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D016040:Lung Transplantation / Q000009:adverse effects*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D061251:Primary Cell Culture; D011446:Prospective Studies; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*; D016896:Treatment Outcome
D059951:HLA-G Antigens; C508609:IL10 protein, human; D016212:Transforming Growth Factor beta; D016753:Interleukin-10