Immunomodulation of Antigen Presenting Cells Promotes Natural Regulatory T Cells That Prevent Autoimmune Diabetes in NOD Mice

Martin J Richer,Marc S Horwitz,Iryna Shanina,Danielle J Lavallée,Geetha P Bansal

doi:10.1371/journal.pone.0031153

Martin J Richer, Marc S Horwitz + Show 3 more

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https://doi.org/10.1371/journal.pone.0031153

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Journal: PloS one	Publication Date: Feb 15, 2012
Citations: 36	License type: CC BY 4.0

Affiliation: University of British Columbia

Abstract

Progression towards type 1 diabetes (T1D) in susceptible patients is linked to a progressive decline in the capacity of regulatory T cells (Treg) to maintain tolerance. As such, therapies aimed at redressing the failing Treg compartment have been the subject of intense investigation. Treg dysfunction in T1D has recently been linked to a reduced capacity of antigen presenting cells (APCs) to maintain Treg function rather than Treg intrinsic defects. This suggests that therapies aimed simply at addressing the failing Treg compartment are unlikely to provide long-term protection. Here, we demonstrate that modulation of the inflammatory status of CD11b+CD11c− APCs favors the upregulation of protective Tregs in a mouse model of T1D. We further demonstrate that reduced expression of the costimulatory molecule CD40 plays a role in this increased immunoregulatory capacity. Strikingly, Treg upregulation resulted exclusively from an increase in natural Tregs rather than the peripheral conversion of conventional T cells. This suggests that modulation of CD11b+ CD11c− APCs inflammatory properties favors the establishment of natural Treg responses that, unlike adaptive Treg responses, are likely to maintain tolerance to a broad range of antigens. As such, modulation of this APC subset represents a potential therapeutic avenue to reestablish peripheral tolerance and protect from autoimmune diseases such as T1D.

Highlights

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease that results from the destruction of the insulin producing b cells of the pancreas
While we observed no significant production of the anti-inflammatory cytokine IL-10, we observed a trend for increased TGF-b production from CD11b+CD11c2 antigen presenting cells (APCs) purified from infected NODTGFb mice this difference did not reach statistical significance (Figure S1)
At day 7 PI, we observed a significant increase in Treg levels in the pancreatic lymph nodes (PLNs) (Figure 4A) and pancreas (Figure 4B) of infected NODCD40KO mice compared to mock-infected mice suggesting an important role for reduced surface expression of CD40 in conferring CD11b+CD11c2 APCs with the capacity to induce Tregs

Summary

Introduction

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease that results from the destruction of the insulin producing b cells of the pancreas. Several reports have demonstrated an important role for regulatory T cells (Tregs) in the maintenance of peripheral tolerance towards pancreatic self-antigens [2,3,4,5,6,7] In both mice and humans a progressive loss of Treg suppressive capacities correlates with disease development [8,9,10,11]. These same APCs present with an inflammatory phenotype that could favor the development of potentially pathogenic IL-17producing T cells (Th17) [15] Taken together, this suggests that therapies aimed at modifying the APC response may allow for the reestablishment of peripheral tolerance and allow for long-term protection from T1D. It has previously been demonstrated that treatment with glatiramer acetate prevents the induction of experimental autoimmune encephalomyelitis (EAE) in mice by inducing ‘‘semi-mature’’ type II monocytes (M2) that in turn induce protective Tregs [16]

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