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Theoretical modeling reveals that regulatory T cells increase T-cell interaction with antigen-presenting cells for stable immune tolerance.

ABSTRACT: The immune system in tolerance maintains cell diversity without responding to self-antigens. Foxp3-expressing CD25+CD4+ regulatory T cells (Tregs) inhibit T-cell activation through various molecular mechanisms. However, several key questions are still not resolved, including how Tregs control the immune response on the basis of their self-skewed T-cell receptor repertoire and how Tregs avoid impeding relevant immunity against pathogens. Here, we show that Tregs promote the proliferation of conventional T cells in the presence of excessive co-stimulation when murine T cells are stimulated in vitro with allogeneic antigen-presenting cells (APCs). Antigen-specific Tregs increase the number of cells interacting with dendritic cells (DCs) by increasing the number of viable DCs and the expression of adhesion molecules on DCs. Theoretical simulations and mathematical models representing the dynamics of T-APC interaction and T-cell numbers in a lymph node indicate that Tregs reduce the dissociation probability of T cells from APCs and increase the new association. These functions contribute to tolerance by enhancing the interaction of low-affinity T cells with APCs. Supporting the theoretical analyses, we found that reducing the T-cell numbers in mice increases the ratio of specific T cells among CD4+ T cells after immunization and effectively induces autoimmune diabetes in non obese diabetes mice. Thus, as a critical function, antigen-specific Tregs stabilize the immune state, irrespective of it being tolerant or responsive, by augmenting T-APC interaction. We propose a novel regulation model in which stable tolerance with large heterogeneous populations proceeds to a specific immune response through a transient state with few populations.

SUBMITTER: Yamaguchi T

PROVIDER: S-EPMC6794947 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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:Antigen-presenting cells (APC) are thought to play an important role in the pathogenesis of drug-induced immune reactions. Various pathological factors can activate APC and therefore influence the immune equilibrium. It is interesting that several diseases have been associated with an increased rate of drug allergy. The aim of this project was to evaluate the impact of such "danger signals" on sulfamethoxazole (SMX) metabolism in human APC (peripheral blood mononuclear cells, Epstein-Barr virus-modified B lymphocytes, monocyte-derived dendritic cells, and two cell lines). APC were incubated with SMX (100 microM-2 mM; 5 min-24 h), in the presence of pathological factors: bacterial endotoxins (lipopolysaccharide and staphylococcal enterotoxin B), flu viral proteins, cytokines [interleukin (IL)-1beta, IL-6, IL-10; tumor necrosis factor-alpha; interferon-gamma; and transforming growth factor-beta], inflammatory molecules (prostaglandin E2, human serum complement, and activated protein C), oxidants (buthionine sulfoximine and H(2)O(2)), and hyperthermia (37.5-39.5 degrees C). Adduct formation was evaluated by enzyme-linked immunosorbent assay and confocal microscopy. SMX-protein adduct formation was time- and concentration-dependent for each cell type tested, in both physiological and danger conditions. A danger environment significantly increased the formation of SMX-protein adducts and significantly shortened the delay for their detection. An additive effect was observed with a combination of danger signals. Dimedone (chemical selectively binding cysteine sulfenic acid) and antioxidants decreased both baseline and danger-enhanced SMX-adduct formation. Various enzyme inhibitors were associated with a significant decrease in SMX-adduct levels, with a pattern varying depending on the cell type and the culture conditions. These results illustrate that danger signals enhance the formation of intracellular SMX-protein adducts in human APC. These findings might be relevant to the increased frequency of drug allergy in certain disease states.

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Theoretical modeling reveals that regulatory T cells increase T-cell interaction with antigen-presenting cells for stable immune tolerance.

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