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Human regulatory T cells inhibit polarization of T helper cells toward antigen-presenting cells via a TGF-beta-dependent mechanism.

ABSTRACT: The molecular mechanisms used by regulatory T cells (Treg) to inhibit the effector phase of adaptive immune responses are still elusive. In the present work, we investigated the possibility that Treg may interfere with a basic biological function of T helper cells (T(H)): polarization of secretory machinery for dedicated help delivery. To address this question, we visualized by confocal microscopy different parameters of activation in T(H) and Treg cells interacting simultaneously with individual antigen-presenting cells (APC). Our results show that, although productive TCR engagement in T(H)/APC conjugates was unaffected by the presence of adjacent Treg, the reorientation of T(H) secretory machinery toward APC was strongly inhibited. Blocking TGF-beta completely reverted Treg induced inhibition of T(H) polarization. Our results identify a previously undescribed mechanism by which Treg inhibit effector T cells. TGF-beta produced by adjacent Treg interferes with polarization of T(H) secretory machinery toward APC, thus affecting a crucial step of T(H)-mediated amplification of the immune response.

SUBMITTER: Esquerre M

PROVIDER: S-EPMC2268174 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Human regulatory T cells inhibit polarization of T helper cells toward antigen-presenting cells via a TGF-beta-dependent mechanism.

Esquerré Michael M Tauzin Baptiste B Guiraud Martine M Müller Sabina S Saoudi Abdelhadi A Valitutti Salvatore S

Proceedings of the National Academy of Sciences of the United States of America 20080211 7

The molecular mechanisms used by regulatory T cells (Treg) to inhibit the effector phase of adaptive immune responses are still elusive. In the present work, we investigated the possibility that Treg may interfere with a basic biological function of T helper cells (T(H)): polarization of secretory machinery for dedicated help delivery. To address this question, we visualized by confocal microscopy different parameters of activation in T(H) and Treg cells interacting simultaneously with individua ...[more]

PMID: 18268354

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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.

Dataset Information

Human regulatory T cells inhibit polarization of T helper cells toward antigen-presenting cells via a TGF-beta-dependent mechanism.

Publications

Human regulatory T cells inhibit polarization of T helper cells toward antigen-presenting cells via a TGF-beta-dependent mechanism.

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