Citations 2
Cutting Edge: Enhanced Antitumor Immunity in ST8Sia6 Knockout Mice
Friedman, David J. , Kizerwetter, Monika , Belmonte, Paul , Rajcula, Matthew, Theodore, Keith, Lee, Hyun Se Kim , Shapiro, Michael J. , Dong, Haidong , Shapiro, Virginia Smith , Kim Lee, Hyun Se , Shapiro, Virginia S , Belmonte, Paul J , Dong, Haidong , Friedman, David , Kizerwetter, Monika , Shapiro, Michael Jeremy
The Journal of Immunology | April 4, 2022 | Volume: 208 | Issue: 8 | Pages: 1845-1850
Abstract Inhibitory receptors have a critical role in the regulation of immunity. Siglecs are a family of primarily inhibitory receptors expressed by immune cells that recognize specific sialic acid modifications on cell surface glycans. Many tumors have increased sialic acid incorporation. Overexpression of the sialyltransferase ST8Sia6 on tumors led to altered immune responses and increased tumor growth. In this study, we examined the role of ST8Sia6 on immune cells in regulating antitumor immunity. ST8Sia6 knockout mice had an enhanced immune response to tumors. The loss of ST8Sia6 promoted an enhanced intratumoral activation of macrophages and dendritic cells, including upregulation of CD40. Intratumoral regulatory T cells exhibited a more inflammatory phenotype in ST8Sia6 knockout mice. Using adoptive transfer studies, the change in regulatory T cell phenotype was not cell intrinsic and depended on the loss of ST8Sia6 expression in APCs. Thus, ST8Sia6 generates ligands for Siglecs that dampen antitumor immunity.
Histone deacetylase 3 represses cholesterol efflux during CD4+ T-cell activation
Wilfahrt, Drew, Philips, Rachael L, Lama, Jyoti, Kizerwetter, Monika , Shapiro, Michael Jeremy, McCue, Shaylene A, Kennedy, Madeleine M, Rajcula, Matthew J, Zeng, Hu, Philips, Rachael L. , Wilfahrt, Drew N. , Lama, Jyoti , Shapiro, Virginia S , Lama, Jyoti, Kizerwetter, Monika , Shapiro, Michael Jeremy, McCue, Shaylene A, Kennedy, Madeleine M, Rajcula, Matthew J, Zeng, Hu
eLife | November 16, 2021 | Volume: 10 | Issue: No issue available | Pages: No page available
After antigenic activation, quiescent naive CD4 + T cells alter their metabolism to proliferate. This metabolic shift increases production of nucleotides, amino acids, fatty acids, and sterols. Here, we show that histone deacetylase 3 (HDAC3) is critical for activation of murine peripheral CD4 + T cells. HDAC3-deficient CD4 + T cells failed to proliferate and blast after in vitro TCR/CD28 stimulation. Upon T-cell activation, genes involved in cholesterol biosynthesis are upregulated while genes that promote cholesterol efflux are repressed. HDAC3-deficient CD4 + T cells had reduced levels of cellular cholesterol both before and after activation. HDAC3-deficient cells upregulate cholesterol synthesis appropriately after activation, but fail to repress cholesterol efflux; notably, they overexpress cholesterol efflux transporters ABCA1 and ABCG1. Repression of these genes is the primary function for HDAC3 in peripheral CD4 + T cells, as addition of exogenous cholesterol restored proliferative capacity. Collectively, these findings demonstrate HDAC3 is essential during CD4 + T-cell activation to repress cholesterol efflux.