Blood Journal
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Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity

  1. Lishomwa C. Ndhlovu1,2,*,
  2. Sandra Lopez-Vergès3,*,
  3. Jason D. Barbour1,
  4. R. Brad Jones4,
  5. Aashish R. Jha2,
  6. Brian R. Long2,
  7. Eric C. Schoeffler2,
  8. Tsuyoshi Fujita1,
  9. Douglas F. Nixon2,, and
  10. Lewis L. Lanier3,5,
  1. 1Hawaii Center for AIDS, Department of Tropical Medicine, University of Hawaii, John A. Burns School of Medicine, Honolulu, HI;
  2. 2Division of Experimental Medicine, Department of Medicine and
  3. 3Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA;
  4. 4Department of Immunology, University of Toronto, Toronto, ON; and
  5. 5Cancer Research Institute, University of California, San Francisco, San Francisco, CA
  1. Presented in oral form at the 14th International Congress of Immunology, Kansai, Japan, August 23, 2010.

Abstract

Natural killer (NK) cells are innate lymphocytes that play an important role against viral infections and cancer. This effect is achieved through a complex mosaic of inhibitory and activating receptors expressed by NK cells that ultimately determine the magnitude of the NK-cell response. The T-cell immunoglobulin– and mucin domain–containing (Tim)–3 receptor was initially identified as a T-helper 1–specific type I membrane protein involved in regulating T-cell responses. Human NK cells transcribe the highest amounts of Tim-3 among lymphocytes. Tim-3 protein is expressed on essentially all mature CD56dimCD16+ NK cells and is expressed heterogeneously in the immature CD56brightCD16 NK-cell subset in blood from healthy adults and in cord blood. Tim-3 expression was induced on CD56brightCD16 NK cells after stimulation with IL-15 or IL-12 and IL-18 in vitro, suggesting that Tim-3 is a maturation marker on NK cells. Whereas Tim-3 has been used to identify dysfunctional T cells, NK cells expressing high amounts of Tim-3 are fully responsive with respect to cytokine production and cytotoxicity. However, when Tim-3 was cross-linked with antibodies it suppressed NK cell–mediated cytotoxicity. These findings suggest that NK-cell responses may be negatively regulated when NK cells encounter target cells expressing cognate ligands of Tim-3.

  • Submitted November 17, 2011.
  • Accepted February 28, 2012.
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