*Purpose: Lung transplantation is a life-saving treatment for terminal lung diseases but long-term outcomes are poor, beginning with possible development of primary graft disease (PGD) in the first few days post-op. PGD is thought to mainly involve hyperactivation of innate immunity, but as CD4+FOXP3+ T-regulatory (Treg) cells can curtail various types of inflammation, we hypothesized that patients who develop PGD might also have dysfunctional Treg cells.

*Methods: We studied pre-Tx blood samples from 78 patients listed for lung transplantation (40% COPD, 20% IPF, 10% non-IPF interstitial lung disease, 10% sarcoidosis, 20% others), 50 of whom received a lung transplant and 18 of whom developed grade 3 PGD.

*Results: We found that patients who developed PGD had a 1.5-fold decrease in Treg function (p<0.05) compared to PGD- patients, and pre-transplant Treg function was inversely correlated with being obese or overweight (ob/ow) (r =-0.3, p = 0.01). Similar inverse correlations between Treg function and ob/ow status were observed in a separate series of pediatric and adult kidney and liver transplant recipients (Pearson r = -0.49, p = 0.0004), pre- and post-transplant. However, not all ob/ow patients developed dysfunctional Treg leading us to explore this point in mice fed a high fat diet. By comparing "metabolically healthy obese" mice with their unhealthy counterparts that had increased IL-18 in their fat, liver and blood, we identified IL-18 as a key factor that directly inhibits Treg suppressive function (2-2.5-fold decrease). Likewise, patients with impaired Treg function had increased levels of IL-18 levels in their blood (3 fold increase, p<0.001). Mechanistically, we found IL-18 decreased total FOXP3 levels in Tregs, impaired FOXP3 dimerization (important for FOXP3 function), increased FOXP3 ubiquitination (enhancing its proteasomal degradation), and derepressed Treg production of IL-1β (3.2 fold) and IL-6 (4.9 fold), (all p<0.05 vs. non-IL-18 treated Treg cells). As a result, IL-18-treated Tregs lose their suppressive function and are unable to control inflammation initiated by innate or adaptive immune cells.

*Conclusions: Increases in circulating levels of IL-18 in ob/ow patients pre-transplant may serve as an important sign of the need to check Treg function, since this combination may lead to increased innate immune activation and risk of PGD, with consequent negative effects on short- and long-term outcomes post-transplant.

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