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Comparison of induced versus natural regulatory T cells of the same TCR specificity for induction of tolerance to an environmental antigen.

Significance Statement

The importance of this work lies in the demonstration that nTreg and iTreg can both contribute to tolerance to a defined antigen, but that they do so differentially.  This outcome applies in the context of the murine model system of asthma that we used, but also as determined using T cells that are conditioned by allergen-presenting IL-10-differentiated immature dendritic cells (DC).  We had shown that analogous human DC10 can similarly convert Teff cells of atopic asthmatic individuals into CD25+Foxp3+ Treg, and that these induced cells are in turn effective in suppressing other Th2 Teff cell responses (Am J Resp Cell Molec Biol 42:190, 2010), but we had not assessed the contributions of nTreg within the CD4+CD25+Foxp3+ T cells to that tolerance.  There are multiple ways of inducing DC with the capacity to in turn foster iTreg differentiation, with IL-10 being one (others include vitamin D3, dexamethasone, etc).  Each of these tolerogenic DC populations would induce Treg with a subtly distinct phenotype (reviewed in Frontiers in Immunology Jan 31, 2014; 5:7 eCollection), such that they would not all be equally comparable.  In order to determine which iTreg population would be best in any one setting we would really need to assess Treg induced in a variety different ways, and then compare each with nTreg.  Another important question that remains unanswered by the present paper is whether nTreg and iTreg that are assessed in alternate settings (e.g., in models of more overtly inflammatory diseases such as inflammatory bowel disease or rheumatoid arthritis) would differentially contribute at the levels as we observed herein.  Or, could they differentially lose their regulatory phenotype under the influence of the local inflammatory environment.  And finally, we did not assess iTreg that do not express CD25 or Foxp3 (e.g., type 1 Treg or Tr1 cells), so that a robust conclusion regarding the relative efficacy of iTreg verus nTreg should really include studies with Tr1 cells in iTreg versus nTreg comparisons.

Huang H, Ma Y, Dawicki W, Zhang X, Gordon JR.

J Immunol. 2013 Aug 1;191(3):1136-43.

Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B4, Canada.

 

Abstract

 Recent evidence shows that natural CD25(+)Foxp3(+) regulatory T cells (nTreg) and induced CD25(+)Foxp3(+) regulatory T cells (iTreg) both contribute to tolerance in mouse models of colitis and asthma, but there is little evidence regarding their relative contributions to this tolerance. We compared the abilities of nTreg and iTreg, both from OVA-TCR-transgenic OTII mice, to mediate tolerance in OVA-asthmatic C57BL/6 mice. The iTreg were differentiated from Th2 effector T cells by exposure to IL-10-differentiated dendritic cells (DC10) in vitro or in vivo, whereas we purified nTreg from allergen-naive mice and exposed them to DC10 before use. Each Treg population was subsequently repurified and tested for its therapeutic efficacy in vitro and in vivo. DC10 engaged the nTreg in a cognate fashion in Forster (or fluorescence) resonance energy transfer assays, and these nTreg reduced in vitro OVA-asthmatic Th2 effector T cell responses by 41-56%, whereas the comparator iTreg reduced these responses by 72-86%. Neutralization of IL-10, but not TGF-{Beta}, eliminated the suppressive activities of iTreg but not nTreg. Delivery of 5 × 10(5) purified nTreg reduced allergen challenge-induced airway IL-4 (p ≤ 0.03) and IL-5 (p ≤ 0.001) responses of asthmatic recipients by ≤ 23% but did not affect airway hyperresponsiveness or IgE levels, whereas equal numbers of iTreg of identical TCR specificity reduced all airway responses to allergen challenge by 82-96% (p ≤ 0.001) and fully normalized airway hyperresponsiveness. These data confirm that allergen-specific iTreg and nTreg have active roles in asthma tolerance and that iTreg are substantially more tolerogenic in this setting.

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