IL-10 diminishes CTLA-4 expression on islet-resident T cells and sustains their activation rather than tolerance.
IL-10, a powerful anti-Th1 cytokine, has shown paradoxical effects against diabetes. The mechanism underlying such variable function remains largely undefined. An approach for controlled mobilization of endogenous IL-10 was applied to the NOD mouse and indicated that IL-10 encounter with diabetogenic T cells within the islets sustains activation, while encounter occurring peripheral to the islets induces tolerance. Insulin beta-chain (INSbeta) 9-23 peptide was expressed on an Ig, and the aggregated (agg) form of the resulting Ig-INSbeta triggered IL-10 production by APCs, and expanded IL-10-producing T regulatory cells. Consequently, agg Ig-INSbeta delayed diabetes effectively in young NOD mice whose pathogenic T cells remain peripheral to the islets. However, agg Ig-INSbeta was unable to suppress the disease in 10-wk-old insulitis-positive animals whose diabetogenic T cells have populated the islets. This is not due to irreversibility of the disease because soluble Ig-INSbeta did delay diabetes in these older mice. Evidence is provided indicating that upon migration to the islet, T cells were activated and up-regulated CTLA-4 expression. IL-10, however, reverses such up-regulation, abolishing CTLA-4-inhibitory functions and sustaining activation of the islet T lymphocytes. Therefore, IL-10 supports T cell tolerance in the periphery, but its interplay with CTLA-4 sustains activation within the islets. As a result, IL-10 displays opposite functions against diabetes in young vs older insulitis-positive mice.
Gregg
Randal K
RK
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212, USA.
Bell
J Jeremiah
JJ
Lee
Hyun-Hee
HH
Jain
Renu
R
Schoenleber
Scott J
SJ
Divekar
Rohit
R
Zaghouani
Habib
H
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007330:Insulin Antibodies / Q000008:administration & dosage / Q000627:therapeutic use; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008969:Molecular Sequence Data; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007166:Immunosuppressive Agents; D007330:Insulin Antibodies; D016753:Interleukin-10