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Regulating the regulators
Inhibitory receptors on T cells, including lymphocyte activation gene 3 (LAG3), serve as brakes that limit immune-mediated damage to the host. LAG3 is expressed by exhausted conventional T cells in the tumor microenvironment and has emerged as a key target for tumor immunotherapy. The role of LAG3 in regulatory T cells (Tregs) has remained unclear. Using a mouse model of autoimmune diabetes, Zhang et al. report that Treg-specific deletion of LAG3 led to enhanced Treg proliferation and reduced the incidence of type 1 diabetes. Their studies highlight the cell-type dependence and context specificity of the role of LAG3 and call for a more holistic assessment of the functions of inhibitory receptors that emerge as targets for tumor immunotherapies.
Abstract
Inhibitory receptors (IRs) 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 IRs on regulatory T cells (Tregs) remains obscure because they could be required for suppressive activity and/or limit Treg function. We evaluated the role of lymphocyte activation gene 3 (LAG3; CD223) on Tregs by generating mice in which LAG3 is absent on the cell surface of Tregs in a murine model of type 1 diabetes. Unexpectedly, mice that lacked LAG3 expression on Tregs exhibited reduced autoimmune diabetes, consistent with enhanced Treg proliferation and function. Whereas the transcriptional landscape of peripheral wild-type (WT) and Lag3-deficient Tregs was largely comparable, substantial differences between intra-islet Tregs were evident and involved a subset of genes and pathways that promote Treg maintenance and function. Consistent with these observations, Lag3-deficient Tregs outcompeted WT Tregs in the islets but not in the periphery in cotransfer experiments because of enhanced interleukin-2–signal transducer and activator of transcription 5 signaling and increased Eos expression. Our study suggests that LAG3 intrinsically limits Treg proliferation and function at inflammatory sites, promotes autoimmunity in a chronic autoimmune-prone environment, and may contribute to Treg insufficiency in autoimmune disease.
- Copyright © 2017, American Association for the Advancement of Science
