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In vivo neutralization of inflammatory cytokines might not be necessary for regulatory T-cell immunotherapy

Nature Reviews Immunology volume 8, page 1 (2008)Cite this article

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We thank Dr Bayry and colleagues for their comments on our recently published Review1. The authors argue that the naturally occurring CD4+CD25+ regulatory T (TReg)-cell population is defective in rheumatoid arthritis and possibly in other autoimmune inflammatory diseases (such as multiple sclerosis and type 1 diabetes) and that therefore adoptive immunotherapy with defective TReg cells isolated from autoimmune patients and expanded ex vivo is unlikely to be efficacious. It is important to highlight that, to date, there is still no formal proof that in vivo TReg cells have an intrinsic defect in chronic inflammatory and autoimmune diseases. As highlighted in our Review, studies investigating the percentages and function of circulating CD4+CD25+ T cells in patient samples have led to conflicting data. These discrepancies might be because the CD4+CD25+ T-cell population can comprise activated T cells that do not display regulatory function, and therefore do not represent a pure TReg-cell population. This is the case in studies performed in patients with type 1 diabetes. The existence of TReg cells with defective suppressor function in patients with type 1 diabetes has been demonstrated by some investigators2,3,4, whereas others5 have shown that TReg cells from such patients are as suppressive as those from normal healthy donors. This latter study was carried out using CD4+CD25hi T cells that were isolated using a fluorescence-activated cell sorter (FACS)5, whereas the former studies used magnetic beads to isolate CD4+CD25+ T cells2,3,4. It is therefore possible that patients with type 1 diabetes do not have defective TReg cells per se, but instead have a higher frequency of contaminating effector T cells in bead-sorted CD4+CD25+ T cells compared with those of healthy individuals. The reported increase in expression of activation markers (such as CD69 and HLA-DR) on CD4+ and CD8+ T cells from patients with type 1 diabetes, both at onset and during the course of the disease, is consistent with this hypothesis6,7. So, only highly purified FACS-sorted CD4+CD25hi T cells from patients with type 1 diabetes display suppressive function in vitro5. Importantly, we have shown that ex vivo culture of TReg cells isolated from type 1 diabetic patients in the presence of rapamycin leads to expanded cells with in vitro regulatory activity that is identical to those of normal donors. These data suggest that, for cells from type 1 diabetic subjects, specific cell-culture conditions can selectively expand functional TReg cells over contaminating effector CD4+CD25+ T cells8.

As an alternative to the ex vivo expansion of TReg cells we also propose in our Review the use of adoptive immunotherapy with inducible regulatory T cells, such as TR1 cells, which are generated in vitro in the presence of the antigen and interleukin-10. This approach overrides the need for isolating and expanding TReg cells from patients with ongoing acute and chronic disease1.

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Authors and Affiliations

  1. Manuela Battaglia is at the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina 58, 20132 Milan, Italy and at the San Raffaele Scientific Institute, Immunology of Diabetes Unit, 20132 Milan, Italy,

    Manuela Battaglia

  2. Maria-Grazia Roncarolo is at the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina 58, 20132 Milan, Italy and at the Vita-Salute San Raffaele University, 20132 Milan, Italy,

    Maria-Grazia Roncarolo

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  1. Manuela Battaglia
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  2. Maria-Grazia Roncarolo
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Battaglia, M., Roncarolo, MG. In vivo neutralization of inflammatory cytokines might not be necessary for regulatory T-cell immunotherapy. Nat Rev Immunol 8, 1 (2008). https://doi.org/10.1038/nri2138-c2

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