| First Author | Garcia Cruz D | Year | 2021 |
| Journal | J Immunol | Volume | 207 |
| Issue | 9 | Pages | 2374-2384 |
| PubMed ID | 34588222 | Mgi Jnum | J:331191 |
| Mgi Id | MGI:6849695 | Doi | 10.4049/jimmunol.2001188 |
| Citation | Garcia Cruz D, et al. (2021) Lymphocyte Activation Gene-3 Regulates Dendritic Cell Metabolic Programing and T Cell Priming Function. J Immunol 207(9):2374-2384 |
| abstractText | Deficiency of lymphocyte activation gene-3 (LAG3) is significantly associated with increased cardiovascular disease risk with in vitro results demonstrating increased TNF-alpha and decreased IL-10 secretion from LAG3-deficient human B lymphoblasts. The hypothesis tested in this study was that Lag3 deficiency in dendritic cells (DCs) would significantly affect cytokine expression, alter cellular metabolism, and prime naive T cells to greater effector differentiation. Experimental approaches used included differentiation of murine bone marrow-derived DCs (BMDCs) to measure secreted cytokines, cellular metabolism, RNA sequencing, whole cell proteomics, adoptive OT-II CD4(+)Lag3 (+/+) donor cells into wild-type (WT) C57BL/6 and Lag3 (-/-) recipient mice, and ex vivo measurements of IFN-gamma from cultured splenocytes. Results showed that Lag3 (-/-) BMDCs secreted more TNF-alpha, were more glycolytic, used fewer fatty acids for mitochondrial respiration, and glycolysis was significantly reduced by exogenous IL-10 treatment. Under basal conditions, RNA sequencing revealed increased expression of CD40 and CD86 and other cytokine-signaling targets as compared with WT. Whole cell proteomics identified a significant number of proteins up- and downregulated in Lag3 (-/-) BMDCs, with significant differences noted in exogenous IL-10 responsiveness compared with WT cells. Ex vivo, IFN-gamma expression was significantly higher in Lag3 (-/-) mice as compared with WT. With in vivo adoptive T cell and in vitro BMDC:T coculture experiments, Lag3 (-/-) BMDCs showed greater T cell effector differentiation and proliferation, respectively, compared with WT BMDCs. In conclusion, Lag3 deficiency in DCs is associated with an inflammatory phenotype that provides a plausible mechanism for increased cardiovascular disease risk in humans with LAG3 deficiency. |
