Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223).
Lymphocyte homeostasis is a central biological process that is tightly regulated. However, its molecular and cellular control is poorly understood. We show that aged mice deficient in lymphocyte activation gene 3 (LAG-3), an MHC class II binding CD4 homologue, have twice as many T cells as wild-type controls. CD4(+) and CD8(+) LAG-3-deficient T cells showed enhanced homeostatic expansion in lymphopenic hosts, which was abrogated by ectopic expression of wild-type LAG-3, but not by a signaling-defective mutant. In addition, in vivo treatment with anti-LAG-3 mAb resulted in enhanced T cell expansion to a level comparable to that in LAG-3-deficient cells. This deregulation of T cell homeostasis also resulted in the expansion of multiple cell types, including B cells, macrophages, granulocytes, and dendritic cells. Lastly, regulatory T cells were dependent on LAG-3 for their optimal control of T cell homeostasis. Our data suggest that LAG-3 negatively regulates T cell homeostasis by regulatory T cell-dependent and independent mechanisms.
Workman
Creg J
CJ
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Vignali
Dario A A
DA
D000375:Aging / Q000235:genetics / Q000276:immunology; D020816:Amino Acid Motifs; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology; D003593:Cytoplasm / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D007275:Injections, Intravenous; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D000093322:Lymphocyte Activation Gene 3 Protein
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015375:Receptors, Interleukin-2; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse