IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage

Abstract

Effective immune responses against pathogens are sometimes accompanied by strong inflammatory reactions. To minimize damage to self, the activation of the immune system also triggers anti-inflammatory circuits. Both inflammatory and anti-inflammatory reactions are normal components of the same immune response, which coordinately fight infections while preventing immune pathology. IL-10 is an important suppressive cytokine, produced by a large number of immune cells in addition to the antigen-driven IL-10-producing regulatory and the naturally occurring suppressor CD4+ T cells, which is a key player in anti-inflammatory immune responses. However, additional mechanisms have evolved to ensure that pathogen eradication is achieved with minimum damage to the host. Here we discuss those mechanisms that operate to regulate effector immune responses.

Figure 1

Layers of regulation of the immune response. At low levels of inflammation (A) both Foxp3⁺ naturally occurring Tregs and Foxp3^– IL-10 Tregs inhibit CD4⁺ T cell proliferation through IL-10–independent, cell contact–dependent mechanisms. (B) Similar mechanisms may control immune responses to self antigens and autoimmune pathologies associated with low-level inflammation such as gastritis. (C) When strong inflammation occurs, with activation of APCs, effector molecules, such as IL-10 and TGF-β, secreted by Tregs are required to control CD4⁺ T cell responses. TLR, Toll-like receptor.

Figure 2

Cross-regulation of effector Th responses and feedback inhibition of naive T cell proliferation. IL-12 produced by the dendritic cell drives Th1 cells (IFN-γ). IL-4 produced by a variety of sources, including in some cases the naive T cell itself, drives Th2 cells to secrete cytokines (IL-4/IL-10). These effector subsets and the cytokines they produce or that drive them inhibit each other’s differentiation. Repetitive activation of effector Th cells with cognate antigen results in the differentiation of regulatory Th cells with inhibitory function via as-yet-unknown mechanisms. Proliferation of naive CD4⁺ T cells is controlled by inhibition of the antigen-presenting cell function of the DCs via both IL-10–dependent and IL-10–independent mechanisms. Green lines with arrows, activation/differentiation; red lines with block, inhibition.