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

2011; American Association of Immunologists; Volume: 187; Issue: 7 Linguagem: Inglês

10.4049/jimmunol.1100714

1550-6606

Maria Bettini, Andrea L. Szymczak-Workman, Karen Forbes, Ashley Castellaw, Mark Selby, Xiaoyu Pan, Charles G. Drake, Alan J. Korman, Dario A.A. Vignali,

Immune Cell Function and Interaction

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 A-specific 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.