Respiratory virus-induced dysregulation of T-regulatory cells leads to chronic rejection.
BACKGROUND
Lower respiratory viral infections predispose to bronchiolitis obliterans syndrome (BOS). In addition, there is emerging evidence to support the role of autoimmunity in the pathogenesis of BOS. Because CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Treg) control autoimmunity, we tested the hypothesis that respiratory virus-induced Treg dysfunction leads to BOS.


METHODS
Treg frequency was monitored using flow cytometry. Apoptosis, cytokines, and antibodies were analyzed using annexin V assay, LUMINEX, and enzyme-linked immunosorbent assay, respectively. Murine studies were performed using the orthotopic tracheal transplant model.


RESULTS
(A) Human studies: Treg troughs (decrease >50% of baseline) were found in 13 (43.3%) of 30 lung transplant recipients. Treg isolated during troughs revealed increased apoptosis (37.8%). Patients with Treg troughs had increased prevalence of antibodies to self-antigens collagen type I (23.1% vs 5.8% pretrough), collagen V (7.7% vs 0%), and k-alpha tubulin (30.7% vs 11.7%, p < 0.01) at 6 months post-trough. Increased number of Treg troughs correlated with more rapid onset of BOS. (B) Murine studies: Infection of tracheal transplant recipients with murine parainfleunza sendai virus led to increased Treg apoptosis (50.5%) in the draining lymph nodes. Vaccination against sendai virus prior to transplant abrogated apoptosis of Treg. In vitro, sendai virus-infected, but not naive, tracheal epithelial cells demonstrated upregulation of FasL (>3.5-fold) and induction of co-cultured Treg apoptosis (5.6-fold increase).


CONCLUSIONS
Respiratory viral infections cause Treg apoptosis which leads to the development of de novo autoimmunity that may play a role in the pathogenesis of BOS.
Bharat
Ankit
A
Department of Surgery/Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Kuo
Elbert
E
Saini
Deepti
D
Steward
Nancy
N
Hachem
Ramsey
R
Trulock
Elbert P
EP
Patterson
G Alexander
GA
Meyers
Bryan F
BF
Mohanakumar
Thalachallour
T
D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity; D001989:Bronchiolitis Obliterans / Q000209:etiology*; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D006084:Graft Rejection / Q000209:etiology*; D006801:Humans; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D029082:Sendai virus / Q000472:pathogenicity*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D014611:Vaccination
D020783:Matrix Metalloproteinase 7