• Tatiana Akimova, Tianyi Zhang, Lanette M Christensen, Zhonglin Wang, Rongxiang Han, Dmitry Negorev, Arabinda Samanta, Isaac E Sasson, Trivikram Gaddapara, Jing Jiao, Liqing Wang, Tricia R Bhatti, Matthew H Levine, Joshua M Diamond, Ulf H Beier, Rebecca A Simmons, Edward Cantu, David S Wilkes, David J Lederer, Michaela Anderson, Jason D Christie, and Wayne W Hancock.
• Division of Transplant Immunology, Department of Pathology and Laboratory Medicine.
• Am. J. Respir. Crit. Care Med. 2021 Nov 1; 204 (9): 1060-1074.

AbstractRationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia-reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did ("inflammatory" HFD) or did not ("healthy" HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs' suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18-driven impairment in Tregs' suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs' suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.

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