Volume 12 Supplement 1
TGF-β2 mediated secretion of sCTLA-4 from regulatory T cells
© Khanolkar et al; licensee BioMed Central Ltd. 2015
Published: 16 April 2015
Cytotoxic T lymphocyte antigen-4 (CTLA-4), a membrane bound inhibitory receptor whose expression is induced on activated T cells, has been established as an important regulator of T cell responses and serves to maintain peripheral tolerance. Additionally, recent characterization of a novel mechanism of extrinsic suppression mediated by the soluble isoform of CTLA-4 (sCTLA-4) has served to further establish the importance of CTLA-4 in maintaining homeostasis of the immune system. Previously, we have shown that selective blockade of sCTLA-4 in patients with metastatic melanoma enhances immune responses including increased antigen-specific proliferation of both CD4+ and CD8+ T cells, compared with an isotype antibody control or pan CTLA-4 blockade. Selective blockade also enhanced T cell effector cytokine responses, notably IFN-γ and IL-17. In this study, we demonstrate a protocol for generating a regulatory T cell population, which is characterised by the production of high levels of sCTLA-4. Treatment of naïve human T cells with TGF-β2 together with an anti-CD3 mAb/IL-2 T cell stimulus increased their capacity to produce high levels of sCTLA-4, while decreasing production of effector cytokines - IFN-γ, IL-17 and IL-10. Furthermore, analysis of these sCTLA-4 producing T cells has shown that they express the T regulatory cell transcription factor – FoxP3. Taken together, our data show that TGF-β2 could serve as an attractive therapeutic tool to alleviate symptoms of autoimmunity through the induction of regulatory T cell populations that secrete immunosuppressive sCTLA-4; while on the other hand, neutralizing the effects of TGF-β2 could also prove beneficial to patients with cancer.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.