Mechanisms regulating enhanced human leukocyte antigen class II-mediated CD4 + T cell recognition of human B-cell lymphoma by resveratrol

Abstract

Malignant B-cells express measurable levels of human leukocyte antigen (HLA) class II proteins, but often escape immune recognition by CD4 + T cells. Resveratrol (Resv) has been the focus of numerous investigations due to its potential chemopreventive and anti-cancer effects, but it has never been tested in the regulation of immune components in B-cell tumors. Here, we show for the first time that Resv treatment enhances HLA class II-mediated immune detection of B-cell lymphomas by altering immune components and class II presentation in tumor cells. Resv treatment induced an up-regulation of both classical and non-classical HLA class II proteins (DR and DM) in B-lymphoma cells. Resv also altered endolysosomal cathepsins (Cat S, B and D) and a thiol reductase (GILT), increasing HLA class II-mediated antigen (Ag) processing in B-cell lymphomas and their subsequent recognition by CD4 + T cells. Mechanistic study demonstrated that Resv treatment activated the recycling class II pathway of Ag presentation through up-regulation of Rab 4B protein expression in B-lymphoma cells. These findings suggest that HLA class II-mediated immune recognition of malignant B-cells can be improved by Resv treatment, thus encouraging its potential use in chemoimmunotherapy of B-cell lymphoma.

Keywords::

• B-cell lymphoma
• resveratrol
• apoptosis
• HLA class II
• Rab 4B
• endocytosis and recycling
• antigen presentation
• CD4 + T cell recognition

Acknowledgements

This work was supported by grants from the National Institutes of Health (CA129560 and CA129560-S1) to A. Haque. The research presented in this article was also supported in part by the Flow Cytometry Shared Resource as part of the Hollings Cancer Center at the Medical University of South Carolina, which is funded by a Cancer Center Support Grant P30 CA138313. We also thank Dr. Janice Blum (Indiana University) for providing us with the B-lymphoma lines, and Drs. L. Xiang, J. Norris, O. Moussa, C. Johnson and A. Das (Medical University of South Carolina) for antibodies and reagents.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.