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.
【저자키워드】 Inflammation, obesity, T cell dysfunction, white adipose tissue, IFNγ, PD-1/PD-L1 immune checkpoints, adipose-tissue-derived mesenchymal stem cells, 【초록키워드】 viruses, SARS-CoV-2, Human, in vitro, immune, PD-L1, T cell, mice, disease, expression, mechanism, immune dysfunction, stem cell, mononuclear cell, increased expression, tissue, individual, secretion, IFNγ, obese, blockade, conditioned media, adipocytes, inducer, adipose, cytokine secretion, analyzed, reduced, occur, demonstrated, individuals, overexpressed, Th1 cell, ASC, cytolytic, visceral, 【제목키워드】 PD-L1, white, STEM,