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Immunomodulation of antigen presenting cells promotes natural regulatory T cells that prevent autoimmune diabetes in NOD mice.

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.

SUBMITTER: Richer MJ

PROVIDER: S-EPMC3280284 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Immunomodulation of antigen presenting cells promotes natural regulatory T cells that prevent autoimmune diabetes in NOD mice.

Richer Martin J MJ Lavallée Danielle J DJ Shanina Iryna I Horwitz Marc S MS

PloS one 20120215 2

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 ad ...[more]

PMID: 22355341

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Project description:Regulatory T cell (Treg)-based therapeutics are receiving increased attention for their potential to treat autoimmune disease and prevent transplant rejection. Adoptively transferred Tregs have shown promise in early clinical trials, but cell-based therapies are expensive and complex to implement, and "off-the-shelf" alternatives are needed. Here, we investigate the potential of artificial antigen presenting cells (aAPCs) fabricated from a blend of negatively charged biodegradable polymer (poly(lactic-co-glycolic acid), PLGA) and cationic biodegradable polymer (poly(beta-amino ester), PBAE) with incorporation of extracellular protein signals 1 and 2 and a soluble released signal 3 to convert naïve T cells to induced Foxp3+ Treg-like suppressor cells (iTregs) both in vitro and in vivo in a biomimetic manner. The addition of PBAE to the aAPC core increased the conjugation efficiency of signal proteins to the particle surface and resulted in enhanced ability to bind to naïve T cells and induce iTregs with potent suppressive function. Furthermore, PLGA/PBAE tolerogenic aAPCs (TolAPCs) supported the loading and sustained release of signal 3 cytokine TGF-β. A single dose of TolAPCs administered intravenously to C57BL/6 J mice resulted in an increased percentage of Foxp3+ cells in the lymph nodes. Thus, PLGA/PBAE TolAPCs show potential as an "off-the-shelf" biomimetic material for tolerance induction. STATEMENT OF SIGNIFICANCE: Regulatory T cells (Tregs) are promising for basic research and translational medicine as they can induce tolerance and have the potential to treat autoimmune diseases such as type 1 diabetes and multiple sclerosis. As cell-based therapies are expensive and difficult to manufacture and implement, non-cellular methods of engineering endogenous Tregs are needed. The research reported here describes a new type of biomimetic particle, tolerogenic artificial antigen presenting cells (TolAPCs) fabricated from a blend of negatively charged biodegradable polymer, poly(lactic-co-glycolic acid), and positively charged biodegradable polymer, poly(beta-amino ester), along with key biomolecular signals: extracellularly presented protein signals 1 and 2 and a soluble released signal 3. These TolAPCs bind to naïve T cells and induce Foxp3+ Treg-like suppressor cells with potent suppressive function. In both in vitro and in vivo studies, it is shown that this non-cellular approach is useful to induce tolerance.

Project description:Autoimmune diseases occur when immune cells fail to develop or lose their tolerance toward self and destroy body's own tissues. Both insufficient negative selection of self-reactive T cells and impaired development of regulatory T cells preventing effector cell activation are believed to contribute to autoimmunity. Genetic predispositions center around the major histocompatibility complex (MHC) class II loci involved in antigen presentation, the key determinant of CD4+ T cell activation. Recent studies suggested that variants in the MHC region also exhibit significant non-additive interaction effects. However, collective interactions involving large numbers of single nucleotide polymorphisms (SNPs) contributing to such effects are yet to be characterized. In addition, relatively little is known about the cell-type-specificity of such interactions in the context of cellular pathways. Here, we analyzed type 1 diabetes (T1D) and rheumatoid arthritis (RA) genome-wide association data sets via large-scale, high-performance computations and inferred collective interaction effects involving MHC SNPs using the discrete discriminant analysis. Despite considerable differences in the details of SNP interactions in T1D and RA data, the enrichment pattern of interacting pairs in reference epigenomes was remarkably similar: statistically significant interactions were epigenetically active in cell-type combinations connecting B cells to T cells and intestinal epithelial cells, with both helper and regulatory T cells showing strong disease-associated interactions with B cells. Our results provide direct genetic evidence pointing to the important roles B cells play as antigen-presenting cells toward CD4+ T cells in the context of central and peripheral tolerance. In addition, they are consistent with recent experimental studies suggesting that the repertoire of B cell-specific self-antigens in the thymus are critical to the effective control of corresponding autoimmune activation in peripheral tissues.

Dataset Information

Immunomodulation of antigen presenting cells promotes natural regulatory T cells that prevent autoimmune diabetes in NOD mice.

Publications

Immunomodulation of antigen presenting cells promotes natural regulatory T cells that prevent autoimmune diabetes in NOD mice.

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