Cutting Edge: TheIdd3Genetic Interval Determines Regulatory T Cell Function through CD11b+CD11c− APC

Abstract

The Idd3 genetic interval confers protection against multiple autoimmune diseases, including type 1 diabetes and experimental autoimmune encephalomyelitis. The favored candidate gene in this interval is Il2, which is polymorphic between susceptible and resistant strains of mice. IL-2 regulates the growth/death of effector T cells as well as the generation/maintenance of regulatory T cells (Tregs), and recent studies have shown that NOD.Idd3 Tregs are more suppressive than their NOD counterparts. We have further dissected the mechanisms underlying the differential suppression by NOD and NOD.Idd3 Tregs and find that it is determined by CD11b ؉ CD11c ؊ APCs. Thus, contrary to what might be expected, our data suggest that the differential suppressive activity of NOD and NOD.Idd3 Tregs is not due to an effect of the Idd3 genetic interval on T cells but rather is due to differences in the APC compartment.

Differential IL-21 signaling in APCs leads to disparate Th17 differentiation in diabetes-susceptible NOD and diabetes-resistant NOD.Idd3 mice

“…Given that NOD.Idd3 mice are protected from T1D and that both IL-2 and IL-21 can modulate the development of induced Tregs and Th17 cells, we assessed the balance of regulatory and pathogenic T cells in these mice. We and others have previously shown that the frequency of Tregs is not significantly different between NOD and diabetes-resistant NOD.Idd3 mice (8,9,23,24). However, in prediabetic mice, we found that the ratio of Tregs/Th17 cells was higher in NOD.Idd3 mice than in NOD mice in both the splenic and pancreatic draining LN compartments ( Figure 2).…”

“…We showed previously that NOD-derived CD11b + APCs inhibit Treg function (9). We now present data that show that this same APC population also promotes Th17 cell differentiation in NOD mice relative to that of NOD.Idd3 congenic mice.…”

“…In this regard, we and others reported that the defective Treg function observed in NOD mice, relative to that of NOD.Idd3 mice, is determined by differences in NOD-derived versus NOD.Idd3-derived APCs (9,10), rather than by intrinsic defects in the Tregs from NOD mice.…”

“…Since we and others previously showed that APCs from NOD and congenic NOD.Idd3 mice have important effects on the suppressive activity of Tregs (9,10) and that Tregs and Th17 cells have a reciprocal relationship (20), we examined the relative contribution of NOD- versus NOD.Idd3-derived APCs on Th17 cell differentiation. By swapping APCs, we found that NOD-derived APCs were more efficient at supporting the differentiation of Th17 cells, irrespective of the source of T cells ( Figure 1B), while NOD.Idd3-derived APCs could not support polarization of Th17 cells as efficiently as NOD-derived APCs.…”

“…Previously, we showed that the differential suppressive activity of Tregs from NOD and NOD.Idd3 mice was regulated by a subset of APCs expressing CD11b and lacking the pan DC marker, CD11c (9). To identify the APC subsets associated with the differential Th17 cell polarization observed between NOD and NOD.Idd3 mice ( Figure 1B), cocultures using APCs depleted of different subsets were set up.…”