Respiratory Virus-Induced Dysregulation of T-Regulatory Cells Leads to Chronic Rejection

Abstract

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. Since CD4+CD25+Foxp3+ T-cell (Treg) control autoimmunity, we tested the hypothesis that respiratory virus-induced Treg dysfunction leads to BOS. Methodology Treg frequency was monitored using flow-cytometry. Apoptosis, cytokines, and antibodies were analyzed using annexin V assay, LUMINEX, and ELISA, respectively. Murine studies were performed using 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% pre-trough), collagen V (7.7% Vs 0%), and k-alpha tubulin (30.7% Vs 11.7%, p<0.01) at 6-months. 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 RVI cause Treg apoptosis which leads to the development of de novo autoimmunity that may play a role in the pathogenesis of BOS.

Lung Injury Combined with Loss of Regulatory T Cells Leads to De Novo Lung-Restricted Autoimmunity

“…Sendai Viral Infection: Sendai Virus (SdV), FUSHIMI strain VR-105, (American Type Culture Collection, Manassas, VA) was stored at −70°C. Titration experiments were performed and a dose of 5,000 egg infectious dose (EID 50 )/animal of SdV (5K) was selected as previously described (27, 29, 30). Mice were anesthesized and 5K SdV diluted with 30 µl of PBS was slowly dropped into their nasal canal.…”

“…The loss of Tregs is associated with lung allograft rejection in both murine and human transplantation, suggesting that maintenance of Treg function is important for downregulating immune responses against allo- and self-antigens (21–26). In a murine model of orthotopic tracheal transplantation, we previously reported that respiratory viruses can upregulate FasL on infected airway epithelial cells, triggering the loss of Tregs (27). Therefore, we hypothesized that both ongoing injury to the lung graft by DSA or gastroesophageal reflux and a concomitant loss of Tregs, triggered for example by respiratory viruses, are necessary for the development of de novo lung-restricted immunity.…”

Lung-Restricted Antibodies Mediate Primary Graft Dysfunction and Prevent Allotolerance after Murine Lung Transplantation

“…There is increasing evidence that alteration in cellular regulation of peripheral tolerance plays a crucial role in chronic allograft rejection (51,52). We have shown that respiratory viruses can induce Treg apoptosis through up-regulation of Fas ligand on the epithelial cells (7). Therefore, ongoing injury from the underlying lung disease combined with loss of Treg can lead to the development of lung-restricted immunity.…”

“…It has recently been shown that T cells specific for lung tissue-restricted sAgs are not deleted by the thymus, but are actively suppressed by thymically derived, antigen-specific forkhead box P3 (Foxp3) 1 regulatory T cells (Tregs) (6). Loss of Tregs, for example, by respiratory viral infections, can lead to the expansion of lung tissue-restricted T cells and development of both cellular and humoral lung-restricted autoimmunity (7). We have previously shown that up to onethird of lung allograft recipients have preexisting IgG antibodies against collagen (Col) type V and K-a1 tubulin (KAT), cryptic sAgs present in the normal lungs (8).…”

Update on lung transplantation: programmes, patients and prospects

“…Equally unclear is why the same virus in the lower respiratory tract of some LTR is associated with minimal symptoms whilst in other cases there is a rapid progression to severe infection, allograft injury and ultimately irreversible lung allograft dysfunction in the form of non-treatment responsive organising pneumonia (e.g. BOOP or FOP) [213][214][215][216]. Interestingly, both BOOP and FOP have been previously described in the setting of acute community acquired pneumonia syndromes and are perhaps related to infectious pathogens [217,218] in the setting of impaired immunity and dysregulated repair; both of which are more common in LTR.…”