Natural killer cells modulate overt autoimmunity to homeostasis in nonobese diabetic mice after anti-CD3 F(ab')2 antibody treatment through secreting transforming growth factor-beta.
Recently, the anti-CD3 antibody has been shown to be a promising candidate for the efficient treatment of overt autoimmunity. However, the mechanisms underlying this effect remain unclear. Our previous studies demonstrated that natural killer (NK)T cells and transforming growth factor (TGF)-beta were key elements in anti-CD3 F(ab')(2)-mediated re-establishment of glucose homeostasis and restoration of self tolerance to islets in type 1 diabetes. In this report, we further investigate the regulatory pathways involved, especially the cellular source of TGF-beta production. The treatment of new-onset nonobese diabetic mice with anti-CD3 F(ab')(2) resulted in a significant increase in the numbers of NK cells in spleen and pancreatic lymph nodes that secrete TGF-beta. Depletion of this cell population with a specific anti-AsGM1 antibody abrogated anti-CD3 F(ab')(2) therapeutic effects and splenic TGF-beta production. When fractionated from recovered mice after CD3 antibody therapy, these NK cells actively suppressed diabetogenic cell proliferation and prevented the cotransfer of diabetes into nonobese diabetic-severe combined immunodeficient mice in a TGF-beta-dependent manner. In addition, the regulatory NKT cells from remitting mice were capable of causing NK cells to exhibit a TGF-beta-producing phenotype by the secretion of the T helper 2 cytokines interleukins 4 and 10. Overall, these data indicate that NK cells are the main source of TGF-beta production after anti-CD3 F(ab')(2) treatment, which are controlled by a population of T helper 2-like NKT cells.
Chen
Guojiang
G
Department of Molecular Immunology, Institute of Basic Medical Sciences, Taiping Road No. 27, Beijing, People's Republic of China.
Han
Gencheng
G
Wang
Jianan
J
Wang
Renxi
R
Xu
Ruonan
R
Shen
Beifen
B
Qian
Jiahua
J
Li
Yan
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015551:Autoimmunity; D017252:CD3 Complex / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000276:immunology; D013154:Spleen / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007140:Immunoglobulin Fab Fragments; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4