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Epigenetic regulation of CD1d-mediated antigen presentation in B cell lymphoma
© Tiper and Webb; licensee BioMed Central Ltd. 2014
Published: 6 November 2014
Tumors frequently alter antigen processing and presentation by major histocompatibility complex (MHC) proteins in order to evade recognition by the immune system. CD1d, a non-polymorphic MHC class I-like molecule, presents lipid antigens to Natural killer T (NKT) cells, which have potent anti-tumor effector functions. NKT cells are able to directly lyse malignant cells and induce anti-tumor responses by modulating other immune cells. Many hematologic malignancies express CD1d and the co-stimulatory proteins needed to induce anti-tumor responses by NKT cells, yet most tumors are poorly immunogenic. Here we sought to test the hypothesis that B cell lymphomas use epigenetic mechanisms to dysregulate CD1d-mediated antigen processing and presentation leading to a functional impairment in the ability of NKT cells to recognize tumors. To assess the functional outcomes of epigenetic modulation, murine and human B cell lymphomas were pretreated with HDAC inhibitors and then we assessed their ability to process and present antigen. Pretreatment with Trichostatin A (TSA) resulted in a dose-dependent increase in CD1d-mediated NKT cell activation by lymphoma cells without altering CD1d or co-stimulatory molecule cell surface expression. Similarly, pretreatment with TSA enhanced MHC class II mediated antigen presentation to CD4+ T cells. In contrast, treatment with the more selective HDACi, MC1568, resulted in an increase in CD1d-mediated NKT cell activation, but did not enhance antigen presentation by HLA-DR4. These data indicate that HDACi differentially modulate CD1d and MHC class II-mediated antigen presentation and suggests a role for multiple HDACs in regulating antigen processing and presentation. Overall, our studies demonstrate the efficacy of HDACi in restoring NKT cell mediated anti-tumor responses and may provide the basis for an NKT cell-based immunotherapeutic strategy that not only enhances the immune response, but also increases the immunogenicity of the tumor itself.
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.