IL-10 Diminishes CTLA-4 Expression on Islet-Resident T Cells and Sustains Their Activation Rather Than Tolerance

Abstract

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 β-chain (INSβ) 9-23 peptide was expressed on an Ig, and the aggregated (agg) form of the resulting Ig-INSβ triggered IL-10 production by APCs, and expanded IL-10-producing T regulatory cells. Consequently, agg Ig-INSβ delayed diabetes effectively in young NOD mice whose pathogenic T cells remain peripheral to the islets. However, agg Ig-INSβ 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-INSβ 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.

A Sudden Decline in Active Membrane-Bound TGF-β Impairs Both T Regulatory Cell Function and Protection against Autoimmune Diabetes

“…Although, this observation sheds light on the loss of function by Tregs operating suppression through mTGF-␤, other mechanisms may be in place for cells operating through cell surface expression of GITR (40,41), production of IL-10 (42, 43), or secreted TGF-␤ (44,45). In fact, we found that Ig-INS␤, a chimera expressing INS␤ 9 -23 peptide expands Tregs that produce IL-10 and protects young animals against diabetes (43). However, at later stages of the disease when the diabetogenic T cells reach the islets and become activated, IL-10 down-regulates their CTLA-4, thus hindering the CTLA-4 inhibitory pathway, to sustain T T cells from untreated NOD male mice were also isolated at 6 wk (e) and 8 wk (f) of age and tested for surface TGF-␤.…”

“…cell activation and nullify the protective function of Tregs (43). Compensatory mechanisms seem to be available, however, because stimulation with anti-CD3 Ab at later stages of the disease mobilizes Tregs that secrete TGF-␤ and protects against the disease (44).…”

Responses of IL-18- and IL-18 receptor-deficient pancreatic islets with convergence of positive and negative signals for the IL-18 receptor

“…In an islet that has been provoked, ␤ cell-derived IL-18 likely engages the IL-18R that is expressed on islet macrophages, which in turn secrete IL-12 and IL-18. The combination of these cytokines is a well-established trigger for IFN␥ production by T cells, which are present in islets (27). In turn, islet macrophages are readily activated by IFN␥ to produce IL-1␤, TNF␣ and nitric oxide.…”

In Trans T Cell Tolerance Diminishes Autoantibody Responses and Exacerbates Experimental Allergic Encephalomyelitis

“…The resulting 91A3-peptide chimeric IgG2b H chain was cotransfected with the parental 91A3 chain into the non-Igproducing SP2/0 myeloma B cell line, and the transfectoma cells producing complete Ig-PLP1 were selected with drugs as described previously (14). Transfection, cloning, sequencing, and purification procedures for Ig-MOG, Ig-MBP3, Ig-PLP2, and Ig-PLP-LR are similar to those used for Ig-PLP1 (5)(6)(7)(8)14).…”