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Interaction of CD99 and its ligands regulates immunoregulatory pathways in NK cells

Myint Myat Thu1,2, Nuchjira Takheaw1,2, Witida Laopajon1,2

  • 1Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.

Frontiers in Immunology
|June 22, 2026
PubMed

Insights

Engagement with CD99 modulates natural killer (NK) cell phenotypes by downregulating natural cytotoxicity receptors (NCRs), especially in the presence of other immune cells. Cytokine production remained unaffected by CD99 interactions.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Medicine

Background:

  • Natural killer (NK) cells are crucial for immune defense against viral infections and tumors.
  • NK cell function relies on a balance of activating and inhibitory receptors.
  • The precise role of CD99 in NK cell receptor modulation requires further elucidation.

Purpose of the Study:

  • To investigate the impact of CD99 engagement on NK cell receptor expression and function.
  • To analyze how CD99 interactions influence NK cell phenotypes under interleukin (IL)-2 stimulation.
  • To determine the context-dependent effects of CD99 on NK cells within different immune microenvironments.

Main Methods:

  • Utilized a recombinant CD99 fusion protein for NK cell stimulation.
  • Analyzed peripheral blood mononuclear cells (PBMCs) and purified NK cells.
  • Employed flow cytometry to assess changes in receptor expression and NK cell phenotypes.

Main Results:

  • CD99 engagement led to the downregulation of natural cytotoxicity receptors (NCRs) on NK cells.
  • Observed differential modulation of NK cell phenotypes in PBMCs versus purified NK cells.
  • No significant alterations in NK cell cytokine production were detected post-CD99 interaction.

Conclusions:

  • CD99-ligand interactions play a role in regulating NK cell activation states and receptor dynamics.
  • The immunomodulatory effects of CD99 on NK cells are context-dependent, influenced by the surrounding immune cell milieu.
  • CD99 contributes to the fine-tuning of NK cell responses under activated conditions.
Keywords:
CD99HIgGactivating receptorsco-stimulatory receptorsnatural cytotoxicity receptors (NCRs)natural killer (NK) cells

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