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Lymphocyte Activation Gene-3 limits regulatory T cell proliferation and function in autoimmune diabetes

ABSTRACT: Inhibitory receptors (Irs) are pivotal in controlling T cell homeostasis because of their intrinsic regulation of conventional T (Tconv) cell proliferation, viability and function. However, the role of Irs on regulatory T (Treg) cells remains obscure, as they could be required for suppressive activity and/or limit Treg cell function. We evaluated the role of Lymphocyte Activation Gene-3 (LAG3, CD223) on Treg cells by generating mice in which LAG3 is absent on the cell surface of Treg cells in a murine model of Type 1 Diabetes. Surprisingly, mice that lacked LAG3 expression on Treg cells exhibited reduced autoimmune diabetes, consistent with enhanced Treg cell proliferation and function. Whereas the transcriptional landscape of peripheral wild-type (WT) and Lag3-deficient Treg cells was largely comparable, substantial differences between intra-islet Treg cells were evident and involved a subset of genes and pathways that promote Treg cell maintenance and function. Consistent with these observations, Lag3-deficient Treg cells out-competed WT Treg cells in the islets but not in the periphery in co-transfer experiments due to enhanced IL2-Stat5 signaling and Eos expression. Our study suggests that LAG3 intrinsically limits Treg cell proliferation and function at inflamed pancreas, promotes autoimmunity in a chronic autoimmune-prone environment and may contribute to Treg cell insufficiency in autoimmune disease

ORGANISM(S): Mus musculus

PROVIDER: GSE94581 | GEO | 2017/03/15

SECONDARY ACCESSION(S): PRJNA371501

REPOSITORIES: GEO

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