In Vitro–expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes

By Q. Tang, K. Henriksen, Mingying Bi, Erik B. Finger, G. Szot, Jianqin Ye, E. Masteller, H. Mcdevitt, M. Bonyhadi, J. Bluestone. Journal of Experimental Medicine, 2004

1,333 citations recorded by the source corpus.

The low number of CD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype, and diverse antigen specificity present major challenges to harnessing this potent tolerogenic population to treat autoimmunity and transplant rejection. In this study, we describe a robust method to expand antigen-specific Tregs from autoimmune-prone nonobese diabetic mice. Purified CD4+ CD25+ Tregs were expanded up to 200-fold in less than 2 wk in vitro using a combination of anti-CD3, anti-CD28, and interleukin 2. The expanded Tregs express a classical cell surface phenotype and function both in vitro and in vivo to suppress effector T cell functions. Most significantly, small numbers of antigen-specific Tregs can reverse diabetes after disease onset, suggesting a novel approach to cellular immunotherapy for autoimmunity.

Subfields: Genetics, Immunology

View Paper: https://www.semanticscholar.org/paper/11254e8e17bd6bac6a1641ac6c19cb39873b7edc

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Shimon Sakaguchi
2. B. Fife
3. M. Krummel
4. J. Bluestone
5. D. Munn
6. A. Mellor

In Immunology

1. Shimon Sakaguchi
2. J. Bluestone
3. B. Beutler
4. C. Lio
5. Q. Tang
6. C. Hsieh
7. B. Fife
8. M. McGeachy

Citations in the corpus

• Foxp3 instability leads to the generation of pathogenic memory T cells in vivo (2009, neutral): “6A)23.”
• A two-step process for thymic regulatory T cell development. (2008, background): “Importantly, self-reactivity appears to be required for Treg cells to maintain self-tolerance and prevent autoimmunity in TCR transgenic and nontransgenic models (Samy et al., 2006; Seddon and Mason, 1999; Taguchi et al., 1994; Tang et al., 2004).”
• Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. (2008, methodology): “showed reduced CD62L expression in newly diabetic mice when compared to Treg cells in 6-week-old prediabetic animals (Figure 2A), suggesting that Treg cells were more activated in the PLN at the time of disease onset (Huehn et al., 2004; Tang et al., 2004 ).”
• The Combined Effects of Tryptophan Starvation and Tryptophan Catabolites Down-Regulate T Cell Receptor ζ-Chain and Induce a Regulatory Phenotype in Naive T Cells1 (2006, background): “In vitroexpanded Ag-specific Tregs can suppress autoimmune diabetes (24).”
• Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. (2006, result): “Similar results have been seen with transfer of purified CD4+CD25+ Tregs (25, 28).”
• Natural Recovery and Protection from Autoimmune Encephalomyelitis: Contribution of CD4+CD25+ Regulatory Cells within the Central Nervous System1 (2005, background): “Tregs that have recently been activated or expanded in vitro are more potent than resting Tregs (27, 31, 32); indeed, the CD4 CD25 cells in the CNS appear phenotypically more highly activated in the CNS than in the LN.”
• Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self (2005, background): “In a therapeutic context, there is accumulating evidence with animal models that natural CD25 + CD4 + T reg cell populations expanded in vivo or ex vivo can be used not only for preventing autoimmune disease but also for treating ongoing autoimmune responses by suppressing the population expan”
• Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice (2006, background): “5 mice' here) routinely prevent and even reverse spontaneous autoimmune diabetes in NOD mic”