Abstract
Based on clinical observations, we have previously shown in a murine model that recipient leukocyte infusion (RLI) induces a host-versus-graft reaction in mixed bone marrow chimeras and that rejection of donor cells leads to a specific antitumor response against recipient malignancies. This response is dependent on T cells and IFN-gamma. We investigated the role of NKT cells (NKTs) in this phenomenon. Depletion of recipient NK1.1(+) cells led to loss of an anti-tumor effect induced by RLI in mixed bone marrow chimeras. In recipients specifically lacking host invariant NKT cells (iNKTs), RLI did not induce an antitumor effect, indicating a critical role for recipient iNKTs. Conversely, specific activation of iNKTs enhanced the anti-tumor effect induced by RLI. Following RLI, recipient iNKTs, NK cells, dendritic cells (DCs), and CD8 T cells were activated. CD8 T cells were the major producers of IFN-gamma. Lack of recipient iNKTs resulted in failure of activation of NK cells and DCs by RLI. Our studies demonstrate a central role for iNKTs in promoting RLI-induced anti-tumor effects and suggest that this pathway involved promotion of the activation of recipient NK cells and DCs.
Highlights
Requirement for NK1.1+ cells for the anti-tumor effect induced by HVG reactions We have shown that recipient leukocyte infusion (RLI)-derived CD8+ T cells are required to obtain maximum anti-tumor effects of RLI
We examined whether NK cells or NKT cell (NKT) are required for the anti-tumor effects induced by HVG reactions
Administration of RLI to established mixed chimera (MC) represents a novel strategy for separating graft-versus-host disease and graft-versustumor effects [4,5,6]
Summary
Our studies demonstrate a central role for iNKTs in promoting RLI-induced anti-tumor effects and suggest that this pathway involved promotion of the activation of recipient NK cells and DCs. The Journal of Immunology, 2010, 185: 2099–2105. Requirement for iNKTs for the anti-tumor effect of RLI To distinguish the possible role of NKTs, we used Ja18 KO mice that are deficient in iNKTs. Ja18 KO chimeric recipients of Ja18 KO-derived RLI (n = 12) demonstrated shorter survival than wildtype chimeric mice receiving wild-type RLI (n = 11) (MST 41.0 versus 67.0 d; p , 0.01), and no survival benefit of Ja18 KO RLI was observed in Ja18 KO recipients (p = 0.93) (Fig. 2A).
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