NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human
Jianhua Yu, … , Susheela Tridandapani, Michael A. Caligiuri
Jianhua Yu, … , Susheela Tridandapani, Michael A. Caligiuri
Published March 1, 2011
Citation Information: J Clin Invest. 2011;121(4):1456-1470. https://doi.org/10.1172/JCI43242.
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NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human

Abstract

IL-15 may have a role in the development of T cell large granular lymphocyte (T-LGL) or NKT leukemias. However, the mechanisms of action and the identity of the cell subset that undergoes leukemic transformation remain elusive. Here we show that in both mice and humans, NKp46 expression marks a minute population of WT NKT cells with higher activity and potency to become leukemic. Virtually 100% of T-LGL leukemias in IL-15 transgenic mice expressed NKp46, as did a majority of human T-LGL leukemias. The minute NKp46+ NKT population, but not the NKp46– NKT population, was selectively expanded by overexpression of endogenous IL-15. Importantly, IL-15 transgenic NKp46– NKT cells did not become NKp46+ in vivo, suggesting that NKp46+ T-LGL leukemia cells were the malignant counterpart of the minute WT NKp46+ NKT population. Mechanistically, NKp46+ NKT cells possessed higher responsiveness to IL-15 in vitro and in vivo compared with that of their NKp46– NKT counterparts. Furthermore, interruption of IL-15 signaling using a neutralizing antibody could prevent LGL leukemia in IL-15 transgenic mice. Collectively, our data demonstrate that NKp46 identifies a functionally distinct NKT subset in mice and humans that appears to be directly susceptible to leukemic transformation when IL-15 is overexpressed. Thus, IL-15 signaling and NKp46 may be useful targets in the treatment of patients with T-LGL or NKT leukemia.

Authors

Jianhua Yu, Takeki Mitsui, Min Wei, Hsiaoyin Mao, Jonathan P. Butchar, Mithun Vinod Shah, Jianying Zhang, Anjali Mishra, Christopher Alvarez-Breckenridge, Xingluo Liu, Shujun Liu, Akihiko Yokohama, Rossana Trotta, Guido Marcucci, Don M. Benson Jr., Thomas P. Loughran Jr., Susheela Tridandapani, Michael A. Caligiuri

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Figure 10

Characterization of NKp46+ NKT cells in human PBMCs.

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Characterization of NKp46+ NKT cells in human PBMCs. (A) Representat...
(A) Representative plot shows that human NKp46+ NKT cells (CD56+CD3+) in peripheral blood of healthy donors represented approximately 1.5% of NKT cells and approximately 0.2% of human lymphocytes (data not shown). (B) Assessment of NKp46+ and NKp46– subsets for surface marker expression. The cell number of the NKp46– NKT subset was roughly equivalent to the number of the minute population of the NKp46+ NKT subset. The numbers above or below each box in each plot are the percentages averaged from at least 3 donors and representing the mean percent positive cells for the surface marker, compared with its isotype control. Mean fluorescence intensity of CD122 is also included and is represented by the numbers in the parenthesis. *P < 0.05. (C) Costimulation of human NKT cells with IL-15 and NKp46 cross-linking shows that FACS-sorted NKp46+ human NKT cells can survive and proliferate for 15 days after costimulation but FACS-sorted NKp46– NKT cells cannot. (D) EdU incorporation assay shows that NKp46+ NKT (CD56+CD3+) cells incorporate higher EdU than NKp46– NKT cells. The assay was conducted on PBMCs freshly isolated from peripheral blood of healthy donors. The percentages in the dot plots indicated EdU+ cells for each subset. (E) IFN-γ intracellular staining indicates that human NKp46+ NKT (CD56+CD3+) cells produce more IFN-γ than NKp46– NKT cells (P < 0.05, n = 3). (A, B, and D) Representative plots from 1 out of at least 3 independent experiments are shown. (C and E) Error bars indicate SD.