The road towards in vitro expansion of Regulatory T cells in an antigen-driven manner

Abstract

Current treatments for Rheumatoid Arthritis aim at remission, often rendering patients immunocompromised. Novel treatments options would therefore be beneficial. It is hypothesized that a dysfunction of Regulatory T cells plays a role in the pathology of Rheumatoid Arthritis. Thus, ex vivo polyclonal culturing of Regulatory T cells, followed by adoptive cell therapy would be a potential new therapy. Hereby, the number and function of Regulatory T cells can be restored. Although this approach shows potential, it comes with limitations, such as a lack of potency and specificity together with a higher risk of generalized immunosuppression. To overcome these, the use of antigen-specific Regulatory T cells would be more beneficial. However, antigen-specific expansion is challenging due to, among others, low available cell numbers. A method in which the high cell yields of polyclonal expansion are combined with the specificity of antigen-specific Regulatory T cells is therefore needed. In our research we move towards a method by which Regulatory T cells can be expanded in an antigen-specific manner. To this end, a protocol for the polyclonal expansion of Regulatory T cells is established using low concentrations of TransAct, high concentrations of rhIL-2 and addition of a TNFR2-agonist, leading to high expansion numbers while retaining a stable phenotype. We show that cells expanded under these conditions can potentially be restimulated in an antigen-specific manner with mammalian B29a, a heat shock protein hypothesized to be involved in Rheumatoid Arthritis. This enables us to obtain a high number of B29a-specific Regulatory T cells from which potentially, in future research, TCRs can be isolated.