CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte–macrophage colony-stimulating factor-dependent fashion

Abstract

CD1d-restricted T cells contribute to tumor protection, but their precise roles remain unclear. Here we show that tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor induce the expansion of CD1d-restricted T cells through a mechanism that involves CD1d and macrophage inflammatory protein 2 expression by CD8␣ ؊ , CD11c ؉ dendritic cells (DCs). The antitumor immunity stimulated by vaccination with irradiated, granulocyte-macrophage colony-stimulating factor-secreting tumor cells was abrogated in CD1d-and J␣281-deficient mice, revealing a critical role for CD1d-restricted T cells in this response. The loss of antitumor immunity was associated with impaired tumorinduced T helper 2 cytokine production, although IFN-␥ secretion and cytotoxicity were preserved. DCs from immunized CD1d-deficient mice showed compromised maturation and function. Together, these results delineate a role for CD1d-restricted T cell-DC cross talk in the shaping of antitumor immunity.

IL-4-Transfected Tumor Cell Vaccines Activate Tumor-Infiltrating Dendritic Cells and Promote Type-1 Immunity

“…This result is expected given the known role for IL-12 as a major inducer of IFN-␥ and IFN-inducible protein 10, both of which play major roles in IL-12 mediated antitumor responses (21,22). Although NKT cells did not appear to be critical mediators or effectors in our IL-4 GT establishment model, antitumor immunity stimulated by vaccination with GM-CSF-secreting tumor cells has been reported to be abrogated in CD1d Ϫ/Ϫ and NKT cell Ϫ/Ϫ mice (23). In this referenced study, the lack of antitumor immunity was accompanied by impaired tumorinduced type 2 cytokine production, although IFN-␥ secretion and cytotoxicity appeared to be preserved.…”

Expression of CD1d Molecules by Human Schwann Cells and Potential Interactions with Immunoregulatory Invariant NK T Cells

“…Several naturally occurring and synthetic lipids have been reported to activate iNKT cells in association with CD1d proteins, the best studied of these being synthetic forms of ␣-galactosylceramide (␣Gal-Cer) (1). The iNKT cells participate in immunoregulation through their ability to rapidly produce large amounts of regulatory cytokines such as IFN-␥ and IL-4, and also by influencing the recruitment and differentiation of dendritic cells (DCs) (2)(3)(4). Their immunoregulatory functions have been emphasized in studies of multiple autoimmune diseases, in which defects of iNKT cell numbers or functions are associated with disease progression (5).…”

“…T he CD1d-restricted invariant NKT (iNKT) 3 cells express a unique invariant TCR-␣ rearrangement (V␣24-J␣18 in humans, V␣14-J␣18 in mice) paired with TCR ␤-chains showing markedly biased usage of one or a few V␤ gene segments (V␤11 in humans, and V␤2, V␤7, and V␤8 in mice) (1). Several naturally occurring and synthetic lipids have been reported to activate iNKT cells in association with CD1d proteins, the best studied of these being synthetic forms of ␣-galactosylceramide (␣Gal-Cer) (1).…”

Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction

“…8 Tumor rejection involves the activities of CD4 ϩ T cells that secrete a broad profile of Th1 and Th2 cytokines, CD8 ϩ cytotoxic T cells, and CD1d-restricted NKT cells. 8,10,11,30 To examine whether immunization also triggers a humoral response, we collected sera from vaccinated mice and evaluated recognition of wild-type RENCA cells with flow cytometry. An anti-mouse pan-IgG secondary antibody was used to measure reactions that typically depend upon CD4 ϩ T-cell help for class switching.…”

“…7 Among these, vaccination with irradiated tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor (GM-CSF) increases the capacity of CD11b ϩ dendritic cells to acquire and present cancer antigens to tumor-reactive CD4 ϩ and CD8 ϩ T cells, CD1d-restricted invariant natural killer T cells (NKT cells), and B cells. [8][9][10][11][12] Several phase 1 and 2 clinical trials of this immunization scheme in patients with various solid and hematologic malignancies demonstrated the generation of a coordinated humoral and cellular anti-tumor response that effectuated substantial tumor necrosis. 13 Although a minority of vaccinated subjects achieved prolonged survival in these studies, most eventually succumbed to progressive disease, implying that additional immune defects remain to be addressed.…”