Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction.
The dynamics of CD4(+) effector T cells (Teff cells) and CD4(+)Foxp3(+) regulatory T cells (Treg cells) during diabetes progression in nonobese diabetic mice was investigated to determine whether an imbalance of Treg cells and Teff cells contributes to the development of type 1 diabetes. Our results demonstrated a progressive decrease in the Treg cell:Teff cell ratio in inflamed islets but not in pancreatic lymph nodes. Intra-islet Treg cells expressed reduced amounts of CD25 and Bcl-2, suggesting that their decline was due to increased apoptosis. Additionally, administration of low-dose interleukin-2 (IL-2) promoted Treg cell survival and protected mice from developing diabetes. Together, these results suggest intra-islet Treg cell dysfunction secondary to defective IL-2 production is a root cause of the progressive breakdown of self-tolerance and the development of diabetes in nonobese diabetic mice.
Tang
Qizhi
Q
Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, Box 0540, San Francisco, CA 94143-0540, USA.
Adams
Jason Y
JY
Penaranda
Cristina
C
Melli
Kristin
K
Piaggio
Eliane
E
Sgouroudis
Evridiki
E
Piccirillo
Ciriaco A
CA
Salomon
Benoit L
BL
Bluestone
Jeffrey A
JA
D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002470:Cell Survival; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism*; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2