Cutting Edge: Accelerated Autoimmune Diabetes in the Absence of LAG-3

Abstract

LAG-3 (CD223) is a CD4 homolog that is required for maximal regulatory T cell function and for the control of CD4+ and CD8+ T cell homeostasis. Lag3−/− NOD mice developed substantially accelerated diabetes with 100% incidence. Adoptive transfer experiments revealed that LAG-3 was primarily responsible for limiting the pathogenic potential of CD4+ T cells, and to a lesser extent CD8+ T cells. Lag3−/− mice exhibited accelerated, invasive insulitis, corresponding to increased CD4+ and CD8+ T cell islet infiltration and intra-islet proliferation. The frequencies of islet antigen reactive chromogranin A-specific CD4+ T cells and IGRP-specific CD8+ T cells were significantly increased in the islets of Lag3−/− mice, suggesting an early expansion of pathogenic clones which is normally restrained by LAG-3. We conclude that LAG-3 is necessary for regulating CD4+ and CD8+ T cell function during autoimmune diabetes, and thus may contribute to limiting autoimmunity in disease-prone environments.

The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects

“…The self-carrying MHC II molecules on T cells may generate a threshold for the initiation of activated T cell-mediated killing, preventing the occurrence of autoimmune activities when no pathogen-derived epitopes are present in the binding groove of MHC I molecules. In accordance with this hypothesis, knocking out LAG-3 could cause accelerated and aggravated autoimmune disease (22). In contrast, the presence of pathogen-derived epitopes in the complex of MHC I molecules could result in the high-affinity binding of MHC I/epitope and TCR, thereby transuding an enhanced signal to invoke the killing and elimination of pathogen-infected somatic cells.…”

“…Similarly to CTLA-4 and PD-1, lymphocyte activation gene-3 (LAG-3), which is a natural high-affinity ligand for MHC class II (MHC II) molecules (16), was shown to play an inhibitory role in regulating T cell immune responses by several studies (17)(18)(19)(20)(21). Accelerated autoimmune diabetes was documented in the absence of LAG-3 in NOD mice (22). LAG-3 acted synergistically with PD-1 to regulate T cell function (23), and the synergistic actions of these two molecules were critical for the prevention of autoimmunity in mice (24).…”

An evolving autoimmune microenvironment regulates the quality of effector T cell restimulation and function

“…Loss of antigenspecific T cell-APC interactions in the draining lymph node in T1D can be a result of antigen-specific regulatory T-cell activity (25) or due to PD-1-PD-L1 interactions (27). A variety of inhibitory receptor-ligand pairs, including but not limited to PD-1-PD-L1/PD-L2, CTLA-4-CD80/CD86, and LAG-3-MHC class II, could be influencing the ability of T cells to recognize their antigen in the islets (27,(31)(32)(33). Our data suggest that these checkpoint receptors are not mediating the changes in the dynamics of T-cell restimulation.…”

Coinhibitory Pathways in Immunotherapy for Cancer

“…LAG-3 inhibitory signals regulate peripheral T cell tolerance by controlling self-reactive effector cells and Tregs (129)(130)(131). LAG-3 deficiency or antibody blockade can markedly accelerate NOD diabetes onset (132). LAG-3 limits the onset and progression of diabetes in NOD mice by inhibiting self-reactive CD4 + and CD8…”