The Role of Natural Killer T Cells in B Cell Lymphoma

Natural killer T (NKT) cells are a unique subset of T cells that recognize glycolipid antigens in the context of CD1d, a non-classical MHC class I-like molecule. NKT cells mount strong anti-tumor responses and are a major focus in developing effective cancer immunotherapy. However, little is known about the regulation of CD1d-mediated antigen 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 can regulate this process, and found that over-expression or induction of Bcl-xL led to increased CD1d-mediated antigen presentation to NKT cells. Conversely, pharmacological inhibition or shRNA-mediated knockdown of Bcl-xL led to decreased antigen presentation. Surface CD1d expression was unchanged by the modulation of Bcl-xL, but its knockdown resulted in reduced CD1d trafficking to LAMP1+ compartments. Furthermore, Rab7, a late endosomal marker was upregulated following Bcl-xL knockdown, and CD1d molecules accumulated in the late endosomes. These results demonstrate that Bcl-xL modulates CD1d-mediated antigen presentation to NKT cells by altering the intracellular trafficking of CD1d. Thus, we have identified a potential tumor recognition mechanism that can impact current therapies targeting the Bcl-2 family, as well as emerging NKT cell based cancer immunotherapeutic strategies. We further studied the role of NKT cells in mantle cell lymphoma, a particularly aggressive form of non-Hodgkin's lymphoma, in vivo, using an IL-14&agr; and c-Myc double-transgenic mouse model. We found that treatment with a single dose of the NKT cell agonist &agr;-Galactosylceramide, increased survival and caused amelioration of disease. Ex vivo restimulation of splenocytes with &agr;-GalCer showed increased IFN-gamma responses, providing some insight into the mechanism underlying the enhanced anti-tumor response following &agr;-GalCer administration. These studies indicate that NKT cells play an important role in mediating an effective immune response to lymphoma, warranting further investigation of the CD1d/NKT system. This small but powerful lymphocyte population bears high potential for translation into the next generation of cancer therapy.