Abstract
The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 was overexpressed in WAT of diet-induced obese mice and was associated with increased expression of PD-1 in visceral but not subcutaneous WAT. Human in vitro cocultures with adipose-tissue-derived mesenchymal stem cells (ASC) and mononuclear cells demonstrated that the presence of ASC harvested from obese WAT (i) enhanced PD-L1 expression as compared with ASC from lean WAT, (ii) decreased Th1 cell cytokine secretion, and (iii) resulted in decreased cytolytic activity towards adipocytes. Moreover, (iv) the implication of PD-L1 in obese ASC-mediated T cell dysfunction was demonstrated through PD-L1 blockade. Finally, (v) conditioned media gathered from these cocultures enhanced PD-L1 expression in freshly differentiated adipocytes, depending on IFNγ. Altogether, our results suggest that PD-L1 is overexpressed in the WAT of obese individuals during IFNγ secretion, leading to T cell dysfunction and notably reduced cytolytic activity. Such a mechanism could shed light on why adipose-tissue-infiltrating viruses, such as SARS-CoV-2, can worsen disease in obese individuals.
Highlights
Effective responses to intracellular pathogens or tumors are usually dependent on Natural killer (NK) cells and/or T cells, especially CD8+ cytotoxic T cells
As white adipose tissue (WAT) is known to initiate inflammation in obese individuals, we investigated whether increased adiposity and inflammation in obesity could result in exhaustion of WAT-infiltrating T cells
Whereas blood T cells from obese individuals or mice have been shown to overexpress the PD-1 checkpoint [19], here we investigated the possibility that WAT-infiltrating T cells could express markers of exhaustion among the obese
Summary
Effective responses to intracellular pathogens or tumors are usually dependent on Natural killer (NK) cells and/or T cells, especially CD8+ cytotoxic T cells. NK or CD8+ cytolytic T cells (CTL), due to increased protein expression of inhibitory receptors such as PD-1, CTLA-4, TIM-3, LAG-3, or TIGIT on T cells, or NKG2A on NK cells, and their respective ligands PD-L1 or PD-L2, CD 155, CD112, CD113, and HLAG/E on antigen-presenting cells [2]. These molecules are called immune checkpoints and the PD-1/PD-L1 axis is known as the strongest exhaustion inducer [3].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
