TY - JOUR
T1 - Lymphocyte activation gene-3 regulates dendritic cell metabolic programing and T cell priming function
AU - Cruz, Dunia Garcia
AU - Giri, Raghavendra R.
AU - Turro, Daylin Gamiotea
AU - Balsbaugh, Jeremy L.
AU - Adler, Adam J.
AU - Rodriguez, Annabelle
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH), National Heart, Lung, and Blood Institute Grant 1RO1HL131862 and a Linda and David Roth Chair in Cardiovascular Research endowment (A.R.). A.J.A. was supported by National Institute of Allergy and Infectious Diseases Grant NIH AI139891.
Publisher Copyright:
Copyright © 2021 by The American Association of Immunologists, Inc.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - Deficiency of lymphocyte activation gene-3 (LAG3) is significantly associated with increased cardiovascular disease risk with in vitro results demonstrating increased TNF-a 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 marroẃderived DCs (BMDCs) to measure secreted cytokines, cellular metabolism, RNA sequencing, whole cell proteomics, adoptive OT-II CD41Lag31/1 donor cells into wild-type (WT) C57BL/6 and Lag3-/-recipient mice, and ex vivo measurements of IFN-g from cultured splenocytes. Results showed that Lag3-/- BMDCs secreted more TNF-a, 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-g 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.
AB - Deficiency of lymphocyte activation gene-3 (LAG3) is significantly associated with increased cardiovascular disease risk with in vitro results demonstrating increased TNF-a 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 marroẃderived DCs (BMDCs) to measure secreted cytokines, cellular metabolism, RNA sequencing, whole cell proteomics, adoptive OT-II CD41Lag31/1 donor cells into wild-type (WT) C57BL/6 and Lag3-/-recipient mice, and ex vivo measurements of IFN-g from cultured splenocytes. Results showed that Lag3-/- BMDCs secreted more TNF-a, 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-g 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.
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U2 - 10.4049/jimmunol.2001188
DO - 10.4049/jimmunol.2001188
M3 - Article
C2 - 34588222
AN - SCOPUS:85119063239
SN - 0022-1767
VL - 207
SP - 2374
EP - 2385
JO - Journal of Immunology
JF - Journal of Immunology
IS - 9
ER -