Bcl-xL regulates CD1d-mediated antigen presentation to NKT cells (APP3P.114)

Abstract

Abstract Natural killer T (NKT) cells are a unique subset of T cells that recognize glycolipid antigens presented by CD1d molecules. Once activated, NKT cells can mount strong anti-tumor responses. However, little is known about the regulation of CD1d-mediated antigen processing and presentation to NKT cells, particularly in the context of B cell lymphoma. Pro-survival factors of the Bcl-2 family, such as Bcl-xL are often upregulated in B cell lymphomas, and are associated with changes in the endocytic pathway, which is paramount for CD1d-mediated antigen presentation. We hypothesized that Bcl-xL regulates this process, and found that over-expression or induction of Bcl-xL led to increased antigen presentation to NKT cells. Conversely, inhibition or knockdown of Bcl-xL led to decreased NKT cell activation. Knockdown of Bcl-xL also resulted in the loss of CD1d trafficking to LAMP1+ compartments. Furthermore, Rab7, a late endosomal marker was upregulated following Bcl-xL knockdown, and CD1d molecules accumulated in the Rab7+ compartment. These results demonstrate that Bcl-xL regulates CD1d-mediated antigen presentation to NKT cells by altering the intracellular localization of CD1d. Thus, we have identified a new pathway involved in antigen presentation that can impact current therapies targeting the Bcl-2 family, as well as emerging NKT cell based cancer immunotherapeutic strategies.