CD28 Costimulation Is Essential for Human T Regulatory Expansion and Function

Golovina, Tatiana; Mikheeva, Tatiana; Suhoski, Megan M.; Aqui, Nicole A.; Tai, Victoria C; Shan, Xiaochuan; Liu, Ronghua; Balcarcel, R. Robert; Fisher, Nancy C.; Levine, Bruce L.; Carroll, Richard G.; Warner, Noel L.; Blazar, Bruce R.; June, Carl H.; Riley, James L.

doi:10.4049/jimmunol.181.4.2855

Cited by 151 publications

(150 citation statements)

References 81 publications

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“…The second novel aspect of our work is the demonstration that TRPM cells preserve their regulatory function even upon in vivo transfer into TBI-treated immunodeficient mice in the absence of any additional rapamycin treatment, thus further supporting their fixed phenotype. The in vivo suppressive potential of FOXP3 + Treg cells, freshly isolated 30 or previously expanded in the presence 31 or absence 32,33 of rapamycin, has already been shown in xeno-graft-versushost disease (GvHD) murine models. However, to our knowledge, to date no experiments have been reported in which only ex vivo-expanded Treg cells have been transferred into TBI-treated NOD/scid mice and subsequently recovered.…”

Section: Discussionmentioning

confidence: 97%

Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells

Tresoldi¹,

Dell’Albani²,

Stabilini³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundThe clinical use of ex vivo-expanded T-regulatory cells for the treatment of T-cell-mediated diseases has gained increasing momentum. However, the recent demonstration that FOXP3 + Tregulatory cells may contain interleukin-17-producing cells and that they can convert into effector cells once transferred in vivo raises significant doubts about their safety. We previously showed that rapamycin permits the ex vivo expansion of FOXP3 + T-regulatory cells while impairing the proliferation of non-T-regulatory cells. Here we investigated the Th17-cell content and the in vivo stability of rapamycin-expanded T-regulatory cells as pertinent aspects of cell-based therapy. Design and MethodsT-regulatory-enriched cells were isolated from healthy volunteers and were expanded ex vivo with rapamycin with a pre-clinical applicable protocol. T-regulatory cells cultured with and without rapamycin were compared for their regulatory activity, content of pro-inflammatory cells and stability. ResultsWe found that CD4+ T cells (i.e., precursor/committed Th17 cells) contaminate the T-regulatory cells cultured ex vivo in the absence of rapamycin. In addition, Th17 cells do not expand when rapamycin-treated T-regulatory cells are exposed to a "Th17-favorable" environment. Rapamycin-expanded T-regulatory cells maintain their in vitro regulatory phenotype even after in vivo transfer into immunodeficient NOD-SCID mice despite being exposed to the irradiation-induced pro-inflammatory environment. Importantly, no additional rapamycin treatment, either in vitro or in vivo, is required to keep their phenotype fixed. ConclusionsThese data demonstrate that rapamycin secures ex vivo-expanded human T-regulatory cells and provide additional justification for their clinical use in future cell therapy-based trials.Key words: T-regulatory cells, ex vivo expansion, rapamycin, cell therapy, T-regulatory-cell stability. + T regulatory cells. Haematologica 2011;96(9):1357-1365

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Section: Discussionmentioning

confidence: 97%

Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells

Tresoldi¹,

Dell’Albani²,

Stabilini³

et al. 2011

Haematologica

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“…However, because of previous barriers in expanding human Ag-specific Treg cells, there has been interest that anti-CD3/CD28-expanded polyclonal Treg cells might be the only approach to generate large numbers of Treg cells for therapeutic applications (43,45,46). Over the last few years, great effort has been made to improve anti-CD3/CD28-based expansion of human polyclonal Treg cells with the goal of improving the yield and purity of the expanded cells (45,(47)(48)(49)(50)(51). Our findings provide an approach to selectively expand alloantigen-specific Treg cells that can serve as a springboard to future development of alloantigen-specific Treg cell-based therapy in humans.…”

Section: Discussionmentioning

confidence: 99%

Direct Expansion of Human Allospecific FoxP3+CD4+ Regulatory T Cells with Allogeneic B Cells for Therapeutic Application

Chen

Delgado

Jensen

et al. 2009

The Journal of Immunology

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Compelling evidence from animal studies has demonstrated that allospecific FoxP3+CD4+ regulatory T (Treg) cells expanded ex vivo can be used as effective therapeutic tools in the treatment of allograft rejection and graft-vs-host disease. Despite the promising results from animal studies, there remain major barriers to developing Treg cell-based immunotherapy in humans. Currently, no effective approach has been established for selective expansion of human allospecific Treg cells ex vivo. Additionally, the very low frequency of Treg cells present in human peripheral blood could pose a formidable challenge to obtaining a sufficient number of Treg cells from a single donor for ex vivo expansion for therapeutic utilization. Extending our recent finding that mouse B cells preferentially induce expansion of alloreactive Treg cells, we report herein that human Treg cells can be expanded ex vivo with allogeneic B cells. The expanded Treg cells express very high levels of FoxP3, maintain anergic phenotype, and are potent suppressors capable of inhibiting the alloproliferation of third-party responder T cells at very low Treg-to-T effector cell ratio in an alloantigen-specific manner. The alloantigen specificity demonstrated by B cell-expanded Treg cells is not determined by the HLA haplotypes of the Treg cells, but it is induced and determined by the haplotype of the B cells used to expand them. Our findings represent a significant advance in the development of Treg cell-based immunotherapy in humans and raise the possibility of using third-party Treg cells for therapeutic applications.

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“…*P < 0.05; **P < 0.01; ***P < 0.001. (32)(33)(34)(35). We attempted to induce Treg proliferation in vitro using many different combinations of anti-CD3 and anti-CD28 antibodies, recombinant IL-2, TGF-β, and retinoic acid with or without TNFR25 agonistic antibody; in all cases, TNFR25 stimulation failed to enhance Treg proliferation in vitro, which indicated that additional signals were required (data not shown and Supplemental Table 1; supplemental material available online with this article; doi:10.1172/JCI42933DS1).…”

Section: Figurementioning

confidence: 99%

Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation

Schreiber¹,

Wolf²,

Tsai³

et al. 2010

J. Clin. Invest.

140

188

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TNF receptor superfamily member 25 (TNFRSF25; also known as DR3, and referred to herein as TNFR25) is constitutively and highly expressed by CD4 + FoxP3 + Tregs. However, its function on these cells has not been determined. Here we used a TNFR25-specific agonistic monoclonal antibody, 4C12, to study the effects of TNFR25 signaling on Tregs in vivo in mice. Signaling through TNFR25 induced rapid and selective expansion of preexisting Tregs in vivo such that they became 30%-35% of all CD4 + T cells in the peripheral blood within 4 days. TNFR25-induced Treg proliferation was dependent upon TCR engagement with MHC class II, IL-2 receptor, and Akt signaling, but not upon costimulation by CD80 or CD86; it was unaffected by rapamycin. TNFR25-expanded Tregs remained highly suppressive ex vivo, and Tregs expanded by TNFR25 in vivo were protective against allergic lung inflammation, a mouse model for asthma, by reversing the ratio of effector T cells to Tregs in the lung, suppressing IL-13 and Th2 cytokine production, and blocking eosinophil exudation into bronchoalveolar fluid. Our studies define what we believe to be a novel mechanism for Treg control and important functions for TNFR25 in regulating autoaggression that balance its known role in enhancing autoimmunity.

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CD28 Costimulation Is Essential for Human T Regulatory Expansion and Function

Cited by 151 publications

References 81 publications

Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells

Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells

Direct Expansion of Human Allospecific FoxP3+CD4+ Regulatory T Cells with Allogeneic B Cells for Therapeutic Application

Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation

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