Expression regulation of co-inhibitory molecules on human natural killer cells in response to cytokine stimulations

Cytokine. 2014 Jan;65(1):33-41. doi: 10.1016/j.cyto.2013.09.016. Epub 2013 Oct 15.


Co-inhibitory molecules have become the key targets in cancer immunotherapy with the strategy of blocking immune checkpoints to reverse the pathogenic regulation of T cells. However, their expression regulations in NK cells, the most important innate immune cells against tumor, remain largely undefined. In this study, we showed that the expressions of co-inhibitors on NK cells, including LAG-3, PD-1, and TIGIT, are differently regulated by cytokines IL-10, IL-12, IL-15, IFN-α, and TGF-β. Among the tested cytokines, IL-12 is the most powerful inducer of LAG-3, and TGF-β is the strongest suppresser of PD-1. Notably, the expression of these co-inhibitors responds to the time course of stimulus progressively. Together, these findings illustrated that the co-inhibitors on NK cells express differently in response to cytokine stimulations of IL-10, IL-12, IL-15, IFN-α, and TGF-β, providing an initial information on the expression regulation of co-inhibitors in human NK cells.

Keywords: Co-inhibitory molecule; Cytokine; Gene regulation; IFN-α; IL; LAG-3; LAG-3-associated protein; LAP; MHC; NK cell; Natural killer cell; PD-1; T cell immunoglobulin and ITIM domain; TGF-β; TIGIT; interferon-α; interleukin; lymphocyte activation gene-3; major histocompatibility complex; natural killer cell; programmed death-1; tumor growth factor-β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interferon-alpha / immunology
  • Interleukin-10 / immunology
  • Interleukin-12 Subunit p35 / immunology
  • Interleukin-15 / immunology
  • Killer Cells, Natural / immunology*
  • Programmed Cell Death 1 Receptor / metabolism*
  • Receptors, Immunologic / metabolism*
  • Transforming Growth Factor beta / immunology


  • Antigens, CD
  • CD223 antigen
  • IL10 protein, human
  • IL12A protein, human
  • IL15 protein, human
  • Interferon-alpha
  • Interleukin-12 Subunit p35
  • Interleukin-15
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • TIGIT protein, human
  • Transforming Growth Factor beta
  • Interleukin-10