Role for IL-10 in Suppression Mediated by Peptide-Induced Regulatory T Cells In Vivo

Abstract

Regulatory CD4+ T cells were induced in the Tg4 TCR transgenic mouse specific for the N-terminal peptide (Ac1-9) of myelin basic protein by intranasal administration of a high-affinity MHC-binding analog (Ac1-9[4Y]). Peptide-induced tolerant cells (PItol) were anergic, failed to produce IL-2, but responded to Ag by secretion of IL-10. PItol cells were predominantly CD25− and CTLA-4+ and their anergic state was reversed by addition of IL-2 in vitro. PItol cells suppressed the response of naive Tg4 cells both in vitro and in vivo. The in vitro suppression mediated by these cells was not reversed by cytokine neutralization and was cell-cell contact-dependent. However, suppression of proliferation and IL-2 production by PItol cells in vivo was abrogated by neutralization of IL-10. These results emphasize an important role for IL-10 in the function of peptide-induced regulatory T cells in vivo and highlight the caution required in extrapolating mechanisms of T regulatory cell function from in vitro studies.

Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis

“…IL-10 + Tr1 cells represent a subset of Tregs, distinct from CD4 + CD25 + regulatory T-cells and with suppressive or regulatory properties (25)(26)(27). IL-10 is produced by many cell types including dendritic cells (28,29), macrophages, monocytes, NK (30,31) and NKT-cells (32) with pleiotropic effects.…”

Inducible costimulator-dependent IL-10 production by regulatory T cells specific for self-antigen

“…This hypothesis is in agreement with Buer's work (34) showing that deeply anergic, but IL-10-producing, T cells were generated in the double-Tg tolerance mouse model in which a specific antigen was expressed in hematopoietic cells. Furthermore, IL-10 production by anergic T cells has also been induced by the repeated administration of superantigen (35,36) or repeated intranasal administration of a high-affinity MHC-binding analog (37).…”

Biologic and immunomodulatory events after CTLA‐4 blockade with ticilimumab in patients with advanced malignant melanoma

“…12 In addition to nT R cells, antigen-induced IL-10-secreting Tr1 cells that inhibit Th1 and Th2 responses via IL-10-dependent mechanisms are possible after chronic antigen exposure. 13,14 Activated CD4 ϩ T cells also express program death-1 (PD-1) receptor, another negative regulator that plays a crucial role in peripheral immune tolerance. 15 Although both CTLA-4 and PD-1 are negative receptors for T-cell activation, they interact with distinct ligands.…”