LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes

Abstract

Inhibitory receptors are pivotal in controlling T cell homeostasis because of their intrinsic regulation of conventional effector T (Tconv) cell proliferation, viability and function. However, the role of Inhibitory receptors 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 increased Eos expression. Our study suggests that LAG3 intrinsically limits Treg cell proliferation and function at inflammatory sites, promotes autoimmunity in a chronic autoimmune-prone environment and may contribute to Treg cell insufficiency in autoimmune disease.

IL-27 targets Foxp3+ Tregs to mediate antiinflammatory functions during experimental allergic airway inflammation

“…Consistent with these findings, we found that Lag3 -/-Tregs adoptively transferred were unable to attenuate allergic inflammation in Treg-depleted recipients even with systemic IL-27 administration, demonstrating a critical role of the IL-27/Lag3 axis in mediating Treg control of allergic inflammation. It was recently reported in the model of autoimmune diabetes that Lag3 intrinsically limits Treg proliferation and function at the sites of inflammation (46). The discrepancy behind these findings is unclear, and the precise contribution of Lag3 in Treg functions needs to be determined.…”

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

“…Moreover, recent studies demonstrated that human Treg cells isolated from individuals with head and neck squamous cell carcinomas (HNSCC) showed enhanced suppressive function compared with Treg cells from matched patient peripheral blood mononuclear cells or healthy donors . Although the exact role of LAG3 on intratumoral Treg cells remains unclear, a recent study using a mouse model of autoimmune diabetes has shown that LAG3 intrinsically limits Treg cell function and survival, while LAG3‐deficient Treg cells substantially delayed the disease onset . Hence, it is possible that LAG3 blockade may limit or augment anti‐tumor immunity depending on the ratio of LAG3 + intratumoral Treg cells versus T effector cells as well as the severity of inflammation in the microenvironment.…”

Co‐expression of LAG3 and TIM3 identifies a potent Treg population that suppresses macrophage functions in colorectal cancer patients

“…The Treg cells express a series of molecules that are associated with the potency of regulatory function. Here, we examined the surface expression levels of two of these molecules, TIM3 and LAG3, in circulating Treg cells. In CD4 + CD25 +/hi T cells, two main populations, including the LAG3 + TIM3 + population and the LAG3 – TIM3 – population could be identified, with very few LAG3‐single positive or TIM3‐single positive cells (Figure A).…”