Lymphocyte activation gene-3 (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 intraislet proliferation. The frequencies of islet Ag-reactive chromogranin Aspecific CD4 + T cells and islet specific glucose-6-phosphatase- specific CD8 + T cells were significantly increased in the islets of Lag3 -/- mice, suggesting an early expansion of pathogenic clones that 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.
ASJC Scopus subject areas
- Immunology and Allergy